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229 results on '"Strom, T.M."'

1. Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer

Author

Saini, M., Schmidleitner, L., Moreno, H.D., Donato, E., Falcone, M., Bartsch, J.M., Vogel, V., Würth, R., Pfarr, N., Espinet, E., Lehmann, M., Königshoff, M., Reitberger, M., Haas, S., Graf, E., Schwarzmayr, T., Strom, T.M., Spaich, S., Sütterlin, M., Schneeweiss, A., Weichert, W., Schotta, G., Reichert, M., Aceto, N., Sprick, M.R., Trumpp, A., Scheel, C.H., and Klein, C.

Subjects
Cancer Research
Abstract

The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.

Published
2023

4. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., Prokisch, H., Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., and Prokisch, H.

Abstract

Contains fulltext : 283137.pdf (Publisher’s version ) (Open Access), BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can

Published
2022

6. A novel homozygous variant in exon 10 of the GALNT3 gene causing hyperphosphatemic familial tumoral calcinosis in a family from North India

Author

Dayal, D., Gupta, S., Kumar, R., Srinivasan, R., Lorenz-Depiereux, B., and Strom, T.M.

Subjects
Galnt3 Gene, Indian Family, Calcinosis Cutis, Hyperphosphatemic Familial Tumoral Calcinosis, Novel Variant
Abstract

Hyperphosphatemic familial tumoral calcinosis (HFTC) is an extremely rare autosomal recessive disorder caused by variants in the GALNT3 (N-acetylgalactosaminyltransferase 3), FGF23 (Fibroblast Growth Factor-23) and αKL (α-Klotho) genes, which results in progressive calcification of soft tissues. We describe the case of a 9-year-old girl who presented with recurrent hard nodular swellings on her feet and knees which intermittently discharged chalky white material. Her younger brother also had a similar condition. Both siblings showed hyperphosphatemia, but the parentsbiochemical parameters were normal. The histological features of the material aspirated from a skin lesion were consistent with tumoral calcinosis. Sanger sequencing identified a novel homozygous non-synonymous sequence variant in exon 10 of the GALNT3 gene (NM_004482.3:c.[1681T>A];[1681T>A], NP_004473.2:p. [Cys561Ser];[Cys561Ser] in the proband and her affected brother. The parents were heterozygous carriers for the same sequence variant. In conclusion, we report a new variant in the GALNT3 gene that caused HFTC in a North Indian family.

Published
2021

7. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author

Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., Senderek, J., Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., and Senderek, J.

Abstract

Item does not contain fulltext, Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Published
2021

8. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Author

Mak, C.C., Doherty, D., Lin, A.E., Vegas, N., Cho, M.T., Viot, G., Dimartino, C., Weisfeld-Adams, J.D., Lessel, D., Joss, S., Li, C., Gonzaga-Jauregui, C., Zarate, Y.A., Ehmke, N., Horn, D., Troyer, C., Kant, S.G., Lee, Y., Ishak, G.E., Leung, G., Pritchard, A. Barone, Yang, S., Bend, E.G., Filippini, F., Roadhouse, C., Lebrun, N., Mehaffey, M.G., Martin, P.M., Apple, B., Millan, F., Puk, O., Hoffer, M.J.V., Henderson, L.B., McGowan, R., Wentzensen, I.M., Pei, S., Zahir, F.R., Yu, M., Gibson, W.T., Seman, A., Steeves, M., Murrell, J.R., Luettgen, S., Francisco, E., Strom, T.M., Amlie-Wolf, L., Kaindl, A.M., Wilson, W.G., Halbach, S., Basel-Salmon, L., Lev-El, N., Denecke, J., Vissers, L.E.L.M., Radtke, K., Chelly, J., Zackai, E., Friedman, J.M., Bamshad, M.J., Nickerson, D.A., Reid, R.R., Devriendt, K., Chae, J.H., Stolerman, E., McDougall, C., Powis, Z., Bienvenu, T., Tan, T.Y., Orenstein, N., Dobyns, W.B., Shieh, J.T., Choi, M., Waggoner, D., Gripp, K.W., Parker, M.J., Stoler, J., Lyonnet, S., Cormier-Daire, V., Viskochil, D., Hoffman, T.L., Amiel, J., Chung, B.H., Gordon, C.T., Mak, C.C., Doherty, D., Lin, A.E., Vegas, N., Cho, M.T., Viot, G., Dimartino, C., Weisfeld-Adams, J.D., Lessel, D., Joss, S., Li, C., Gonzaga-Jauregui, C., Zarate, Y.A., Ehmke, N., Horn, D., Troyer, C., Kant, S.G., Lee, Y., Ishak, G.E., Leung, G., Pritchard, A. Barone, Yang, S., Bend, E.G., Filippini, F., Roadhouse, C., Lebrun, N., Mehaffey, M.G., Martin, P.M., Apple, B., Millan, F., Puk, O., Hoffer, M.J.V., Henderson, L.B., McGowan, R., Wentzensen, I.M., Pei, S., Zahir, F.R., Yu, M., Gibson, W.T., Seman, A., Steeves, M., Murrell, J.R., Luettgen, S., Francisco, E., Strom, T.M., Amlie-Wolf, L., Kaindl, A.M., Wilson, W.G., Halbach, S., Basel-Salmon, L., Lev-El, N., Denecke, J., Vissers, L.E.L.M., Radtke, K., Chelly, J., Zackai, E., Friedman, J.M., Bamshad, M.J., Nickerson, D.A., Reid, R.R., Devriendt, K., Chae, J.H., Stolerman, E., McDougall, C., Powis, Z., Bienvenu, T., Tan, T.Y., Orenstein, N., Dobyns, W.B., Shieh, J.T., Choi, M., Waggoner, D., Gripp, K.W., Parker, M.J., Stoler, J., Lyonnet, S., Cormier-Daire, V., Viskochil, D., Hoffman, T.L., Amiel, J., Chung, B.H., and Gordon, C.T.

Abstract

Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access), MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Published
2020

9. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

Author

Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., Opladen, T., Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., and Opladen, T.

Abstract

Contains fulltext : 220941.pdf (Publisher’s version ) (Closed access), PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

Published
2020

10. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author

Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), Bhoj, E.J. (Elizabeth J.), Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), and Bhoj, E.J. (Elizabeth J.)

Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020
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11. Human RAD50 deficiency: Confirmation of a distinctive phenotype

Author

Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), Mancini, G.M.S. (Grazia), Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), and Mancini, G.M.S. (Grazia)

Abstract

DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the pat

Published
2020
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12. Identification of coexpressed gene clusters in a comparative analysis of transcriptome and proteome in mouse tissues

Author

Mijalski, T., Harder, A., Halder, T., Kersten, M., Horsch, M., Strom, T.M., Liebscher, H.V., Lottspeich, F., de Angelis, M. Hrabe, and Beckers, J.

Subjects
Gene expression -- Research, Science and technology
Abstract

A major advantage of the mouse model lies in the increasing information on its genome, transcriptome, and proteome, as well as in the availability of a fast growing number of targeted and induced mutant alleles. However, data from comparative transcriptome and proteome analyses in this model organism are very limited. We use DNA chip-based RNA expression profiling and 2D gel electrophoresis, combined with peptide mass fingerprinting of liver and kidney, to explore the feasibility of such comprehensive gene expression analyses. Although protein analyses mostly identify known metabolic enzymes and structural proteins, transcriptome analyses reveal the differential expression of functionally diverse and not yet described genes. The comparative analysis suggests correlation between transcriptional and translational expression for the majority of genes. Significant exceptions from this correlation confirm the complementarities of both approaches. Based on RNA expression data from the 200 most differentially expressed genes, we identify chromosomal colocalization of known, as well as not yet described, gene clusters. The determination of 29 such clusters may suggest that coexpression of colocalizing genes is probably rather common. coexpression and colocalization | comparative expression profiles

Published
2005

13. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome

Author

Koolen, D.A., Sharp, A.J., Hurst, J.A., Firth, H.V., Knight, S.J.L., Goldenberg, A., Saugier-Veber, P., Pfundt, R., Vissers, L.E.L.M., Destree, A., Grisart, B., Rooms, L., Van der Aa, N., Field, M., Hackett, A., Bell, K., Nowaczyk, M.J.M., Mancini, G.M.S., Poddighe, P.J., Schwartz, C.E., Rossi, E., De Gregori, M., Antonacci-Fulton, L.L., McLellan, M.D., II, Garrett, J.M., Wiechert, M.A., Miner, T.L., Crosby, S., Ciccone, R., Willatt, L., Rauch, A., Zenker, M., Aradhya, S., Manning, M.A., Strom, T.M., Wagenstaller, J., Krepischi-Santos, A.C., Vianna-Morgante, A.M., Rosenberg, C., Price, S.M., Stewart, H., Shaw-Smith, C., H.G. Brunner, Wilkie, A.O.M., Veltman, J.A., Zuffardi, O., Eichler, E.E., and de Vries, B.B.A.

Subjects
Chromosomes -- Research, Chromosomes -- Physiological aspects, Genetic disorders -- Research, Genetic disorders -- Physiological aspects, Mental retardation -- Research, Mental retardation -- Genetic aspects, Health
Published
2008

14. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Author

Kenna, K.P., van Doormaal, P.T.C., Dekker, A.M., Ticozzi, N., Kenna, B.J., Diekstra, F.P., van Rheenen, W., van Eijk, K.R., Jones, A.R., Keagle, P., Shatunov, A., Sproviero, W., Smith, B.N., van Es, M.A., Topp, S.D., Kenna, A., Miller, J.W., Fallini, C., Tiloca, C., McLaughlin, R.L., Vance, C., Troakes, C., Colombrita, C., Mora, G., Calvo, A., Verde, F., Al-Sarraj, S., King, A., Calini, D., de Belleroche, J., Baas, F., van der Kooi, A.J., de Visser, M., ten Asbroek, A.L.M.A., Sapp, P.C., McKenna-Yasek, D., Polak, M., Asress, S., Muñoz-Blanco, J.L., Strom, T.M., Meitinger, T., Morrison, K.E., D'Alfonso, S., Mazzini, L., Comi, G.P., Del Bo, R., Ceroni, M., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Corti, S., Cereda, C., Corrado, L., Sorarù, G., Lauria, G., Williams, K.L., Leigh, P.N., Nicholson, G.A., Blair, I.P., Leblond, C.S., Dion, P.A., Rouleau, G.A., Pall, H., Shaw, P.J., Turner, M.R., Talbot, K., Taroni, F., Boylan, K.B., Van Blitterswijk, M., Rademakers, R., Esteban-Pérez, J., García-Redondo, A., Van Damme, P., Robberecht, W., Chio, A., Gellera, C., Drepper, C., Sendtner, M., Ratti, A., Glass, J.D., Mora, J.S., Basak, N.A., Hardiman, O., Ludolph, A.C., Andersen, P.M., Weishaupt, J.H., Brown, R.H., Al-Chalabi, A., Silani, V., Shaw, C.E., van den Berg, L.H., Veldink, J.H., Landers, J.E., Medical Research Council (MRC), Human Genetics, Neurology, ANS - Neurodegeneration, and SLAGEN Consortium

Subjects
0301 basic medicine, medicine.medical_specialty, Genomics, Biology, medicine.disease_cause, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Genetics, medicine, Humans, Comparative Study, Exome, Genetic Predisposition to Disease, SLAGEN Consortium, Risk factor, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, Netherlands, Mutation, Amyotrophic Lateral Sclerosis, Case-control study, 11 Medical And Health Sciences, 06 Biological Sciences, medicine.disease, 3. Good health, NIMA-Related Kinase 1, 030104 developmental biology, RC0346, Case-Control Studies, Medical genetics, Human medicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology. ispartof: Nature Genetics vol:48 issue:9 pages:1037-+ ispartof: location:United States status: published

Published
2016

15. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

Author

Verheije, R., Kupchik, G.S., Isidor, B., Kroes, H.Y., Lynch, S.A., Hawkes, L., Hempel, M., Gelb, B.D., Ghoumid, J., D’Amours, G., Chandler, K., Dubourg, C., Loddo, S., Tümer, Z., Shaw-Smith, C., Nizon, M., Shevell, M., Van Hoof, E., Anyane-Yeboa, K., Cerbone, G., Clayton-Smith, J., Cogné, B., Corre, P., Corveleyn, A., De Borre, M., Hjortshøj, T.D., Fradin, M., Gewillig, M., Goldmuntz, E., Hens, G., Lemyre, E., Journel, H., Kini, U., Kortüm, F., Le Caignec, C., Novelli, A., Odent, S., Petit, F., Revah-Politi, A., Stong, N., Strom, T.M., van Binsbergen, E., DDD Study, Devriendt, K., and Breckpot, J.

Subjects
Male, Loss of Function Mutation, Intellectual disability, Genetics(clinical), Non-U.S. Gov't, Child, Genetics (clinical), Heart Defects, Genetics, 0303 health sciences, Congenital/genetics, Research Support, Non-U.S. Gov't, 030305 genetics & heredity, Syndrome, Phenotype, Heart Defects, Congenital/genetics, Cleft Palate, Child, Preschool, Female, Haploinsufficiency, Heart Defects, Congenital, Heterozygote, Adolescent, Transcription Factors/genetics, Locus (genetics), Research Support, Article, N.I.H, 03 medical and health sciences, Young Adult, Research Support, N.I.H., Extramural, Cleft Palate/genetics, Intellectual Disability, medicine, Journal Article, Humans, Preschool, Gene, Loss function, Homeodomain Proteins, business.industry, Chromosome, Extramural, Heterozygote advantage, medicine.disease, Intellectual Disability/genetics, Homeodomain Proteins/genetics, business, Transcription Factors
Abstract

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype–phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.

Published
2018

16. De Novo and Inherited Loss-of-Function Variants in TLK2 : Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology

Subjects
Tousled-like, Facial Averaging, Haploinsufficiency, Intellectual Disability, Kinase, Adult, Male, Adolescent, kinase, viruses, Inheritance Patterns, Medizin, Translocation, Genetic, Cell Line, Young Adult, Loss of Function Mutation, Report, Humans, RNA, Messenger, Child, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Infant, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Female, Protein Kinases, facial averaging, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.

Published
2018

17. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), Wortmann, S.B. (S.), Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), and Wortmann, S.B. (S.)

Abstract

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and s

Published
2018
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18. Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

Author

Shashi, V., Magiera, M.M., Klein, D., Zaki, M., Schoch, K., Rudnik-Schoneborn, S., Norman, A., Neto, O. Abath, Dusl, M., Yuan, X., Bartesaghi, L., Marco, P. De, Alfares, A.A., Marom, R., Arold, Stefan T., Guzman-Vega, F.J., Pena, L.D., Smith, E.C., Steinlin, M., Babiker, M.O., Mohassel, P., Foley, A.R., Donkervoort, S., Kaur, R., Ghosh, P.S., Stanley, V., Musaev, D., Nava, C., Mignot, C., Keren, B., Scala, M., Tassano, E., Picco, P., Doneda, P., Fiorillo, C., Issa, M.Y., Alassiri, A., Alahmad, A., Gerard, A., Liu, P, Yang, Y., Ertl-Wagner, B., Kranz, P.G., Wentzensen, I.M., Stucka, R., Stong, N., Allen, A.S., Goldstein, D.B, Schoser, B., Rosler, K.M., Alfadhel, M., Capra, V., Chrast, R., Strom, T.M., Kamsteeg, E.J., Bonnemann, C.G., Gleeson, J.G., Martini, R., Janke, C., Senderek, J., Shashi, V., Magiera, M.M., Klein, D., Zaki, M., Schoch, K., Rudnik-Schoneborn, S., Norman, A., Neto, O. Abath, Dusl, M., Yuan, X., Bartesaghi, L., Marco, P. De, Alfares, A.A., Marom, R., Arold, Stefan T., Guzman-Vega, F.J., Pena, L.D., Smith, E.C., Steinlin, M., Babiker, M.O., Mohassel, P., Foley, A.R., Donkervoort, S., Kaur, R., Ghosh, P.S., Stanley, V., Musaev, D., Nava, C., Mignot, C., Keren, B., Scala, M., Tassano, E., Picco, P., Doneda, P., Fiorillo, C., Issa, M.Y., Alassiri, A., Alahmad, A., Gerard, A., Liu, P, Yang, Y., Ertl-Wagner, B., Kranz, P.G., Wentzensen, I.M., Stucka, R., Stong, N., Allen, A.S., Goldstein, D.B, Schoser, B., Rosler, K.M., Alfadhel, M., Capra, V., Chrast, R., Strom, T.M., Kamsteeg, E.J., Bonnemann, C.G., Gleeson, J.G., Martini, R., Janke, C., and Senderek, J.

Abstract

Item does not contain fulltext, A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

Published
2018

20. Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease

Author

Schormair, B., Kemlink, D., Mollenhauer, B., Fiala, O., Machetanz, G., Roth, J., Berutti, R., Strom, T.M., Haslinger, B., Trenkwalder, C., Zahorakova, D., Martasek, P., Ruzicka, E., and Winkelmann, J.

Subjects
Exome, Genetic Testing, Parkinson Disease, Vps13c
Abstract

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

Published
2017

21. Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies

Author

Feichtinger, R.G., Brunner-Krainz, M., Alhaddad, B., Wortmann, S.B., Kovács-Nagy, R., Stojakovic, T., Erwa, W., Resch, B., Windischhofer, W., Verheyen, S., Uhrig, S., Windpassinger, C., Locker, F., Makowski, C., Strom, T.M., Meitinger, T., Prokisch, H., Sperl, W., Haack, T.B., and Mayr, J.A.

Subjects
Article Subject, lcsh:Cytology, lcsh:QH573-671
Abstract

Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in UQCC2, leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation.

Published
2017

22. Diagnostic exome sequencing in early-onset Parkinson's disease confirmsVPS13Cas a rare cause of autosomal-recessive Parkinson's disease

Author

Schormair, B., primary, Kemlink, D., additional, Mollenhauer, B., additional, Fiala, O., additional, Machetanz, G., additional, Roth, J., additional, Berutti, R., additional, Strom, T.M., additional, Haslinger, B., additional, Trenkwalder, C., additional, Zahorakova, D., additional, Martasek, P., additional, Ruzicka, E., additional, and Winkelmann, J., additional

Published
2018
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23. Mutations in RAB28, Encoding a Farnesylated Small GTPase, Are Associated with Autosomal-Recessive Cone-Rod Dystrophy

Author

Roosing, S., Rohrschneider, K., Beryozkin, A., Sharon, D., Weisschuh, N., Staller, J., Kohl, S., Zelinger, L., Peters, T.A., Neveling, K., Strom, T.M., Disease, C. European Retina, Born, L.I. van den, Hoyng, C.B., Klaver, C.C., Roepman, R., Wissinger, B., Banin, E., Cremers, F.P.M., Hollander, A.I. den, and Ophthalmology

Subjects
Genetics and epigenetic pathways of disease [NCMLS 6], genetic structures, Visual Acuity, GTPase, Retinal Pigment Epithelium, Retinal Rod Photoreceptor Cells, Evaluation of complex medical interventions Genomic disorders and inherited multi-system disorders [NCEBP 2], Genetics(clinical), Child, Genetics (clinical), Genetics, 0303 health sciences, 030305 genetics & heredity, Homozygote, Chromosome Mapping, Disease gene identification, Pedigree, Isoenzymes, Protein Transport, medicine.anatomical_structure, Codon, Nonsense, Retinitis Pigmentosa, Adult, Adolescent, Nonsense mutation, Protein Prenylation, Genes, Recessive, Biology, Retina, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Report, Retinitis pigmentosa, Ciliary rootlet, medicine, Animals, Humans, Genetic Predisposition to Disease, Cilia, Photoreceptor Connecting Cilium, Genetic Association Studies, 030304 developmental biology, Retinal pigment epithelium, Genetics and epigenetic pathways of disease Plasticity and memory [NCMLS 6], medicine.disease, Molecular biology, eye diseases, Rats, Alternative Splicing, Gene Expression Regulation, rab GTP-Binding Proteins, Protein prenylation, Rab, sense organs, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6]
Abstract

Item does not contain fulltext The majority of the genetic causes of autosomal-recessive (ar) cone-rod dystrophy (CRD) are currently unknown. A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD. All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram. RAB28 encodes a member of the Rab subfamily of the RAS-related small GTPases. Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report. Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors. Analogous to the function of other RAB family members, RAB28 might be involved in ciliary transport in photoreceptor cells. This study reveals a crucial role for RAB28 in photoreceptor function and suggests that mutations in other Rab proteins may also be associated with retinal dystrophies.

Published
2013

24. Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

Author

Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., Wevers, R.A., Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., and Wevers, R.A.

Abstract

Contains fulltext : 169752.pdf (publisher's version ) (Closed access), Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.

Published
2017

25. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism

Author

Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., Wieczorek, D., Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., and Wieczorek, D.

Abstract

Contains fulltext : 169702.pdf (publisher's version ) (Closed access), The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Published
2017

26. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Author

Habarou, F., Hamel, Y., Haack, T.B., Feichtinger, R.G., Lebigot, E., Marquardt, I., Busiah, K., Laroche, C., Madrange, M., Grisel, C., Pontoizeau, C., Eisermann, M., Boutron, A., Chretien, D., Chadefaux-Vekemans, B., Barouki, R., Bole-Feysot, C., Nitschke, P., Goudin, N., Boddaert, N., Nemazanyy, I., Delahodde, A., Kolker, S., Rodenburg, R.J.T., Korenke, G.C., Meitinger, T., Strom, T.M., Prokisch, H., Rotig, A., Ottolenghi, C., Mayr, J.A., Lonlay, P. de, Habarou, F., Hamel, Y., Haack, T.B., Feichtinger, R.G., Lebigot, E., Marquardt, I., Busiah, K., Laroche, C., Madrange, M., Grisel, C., Pontoizeau, C., Eisermann, M., Boutron, A., Chretien, D., Chadefaux-Vekemans, B., Barouki, R., Bole-Feysot, C., Nitschke, P., Goudin, N., Boddaert, N., Nemazanyy, I., Delahodde, A., Kolker, S., Rodenburg, R.J.T., Korenke, G.C., Meitinger, T., Strom, T.M., Prokisch, H., Rotig, A., Ottolenghi, C., Mayr, J.A., and Lonlay, P. de

Abstract

Item does not contain fulltext, Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (alpha-oxoglutarate dehydrogenase [alpha-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, alpha-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, alpha-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

Published
2017

27. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability

Author

Bramswig, N.C., Ludecke, H.J., Hamdan, F.F., Altmuller, J., Beleggia, F., Elcioglu, N.H., Freyer, C., Gerkes, E.H., Demirkol, Y.K., Knupp, K.G., Kuechler, A., Li, Y., Lowenstein, D.H., Michaud, J.L., Park, K., Stegmann, A.P., Veenstra-Knol, H.E., Wieland, T., Wollnik, B., Engels, H., Strom, T.M., Kleefstra, T., Wieczorek, D., Bramswig, N.C., Ludecke, H.J., Hamdan, F.F., Altmuller, J., Beleggia, F., Elcioglu, N.H., Freyer, C., Gerkes, E.H., Demirkol, Y.K., Knupp, K.G., Kuechler, A., Li, Y., Lowenstein, D.H., Michaud, J.L., Park, K., Stegmann, A.P., Veenstra-Knol, H.E., Wieland, T., Wollnik, B., Engels, H., Strom, T.M., Kleefstra, T., and Wieczorek, D.

Abstract

Contains fulltext : 174755.pdf (publisher's version ) (Closed access), Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.

Published
2017

28. CAD mutations and uridine-responsive epileptic encephalopathy

Author

Koch, J., Mayr, J.A., Alhaddad, B., Rauscher, C., Bierau, J., Kovacs-Nagy, R., Coene, K.L.M., Bader, I., Holzhacker, M., Prokisch, H., Venselaar, H., Wevers, R.A., Distelmaier, F., Polster, T., Leiz, S., Betzler, C., Strom, T.M., Sperl, W., Meitinger, T., Wortmann, S.B., Haack, T.B., Koch, J., Mayr, J.A., Alhaddad, B., Rauscher, C., Bierau, J., Kovacs-Nagy, R., Coene, K.L.M., Bader, I., Holzhacker, M., Prokisch, H., Venselaar, H., Wevers, R.A., Distelmaier, F., Polster, T., Leiz, S., Betzler, C., Strom, T.M., Sperl, W., Meitinger, T., Wortmann, S.B., and Haack, T.B.

Abstract

Contains fulltext : 169910.pdf (publisher's version ) (Closed access), Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.

Published
2017

29. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author

Lessel, D., Schob, C., Kury, S., Reinders, M.R.F., Harel, T., Eldomery, M.K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A.P., Gerkes, E.H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T.M., Rosenfeld, J.A., Yang, Y, Posey, J.E., Immken, L., Oundjian, N., Helbig, K.L., Meeks, N., Zegar, K., Morton, J., Schieving, J.H., Claasen, A., Huentelman, M., Narayanan, V., Ramsey, K., Brunner, H.G., Elpeleg, O., Mercier, S., Bezieau, S., Kubisch, C., Kleefstra, T., Kindler, S., Lupski, J.R., Kreienkamp, H.J., Lessel, D., Schob, C., Kury, S., Reinders, M.R.F., Harel, T., Eldomery, M.K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A.P., Gerkes, E.H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T.M., Rosenfeld, J.A., Yang, Y, Posey, J.E., Immken, L., Oundjian, N., Helbig, K.L., Meeks, N., Zegar, K., Morton, J., Schieving, J.H., Claasen, A., Huentelman, M., Narayanan, V., Ramsey, K., Brunner, H.G., Elpeleg, O., Mercier, S., Bezieau, S., Kubisch, C., Kleefstra, T., Kindler, S., Lupski, J.R., and Kreienkamp, H.J.

Abstract

Contains fulltext : 182457.pdf (publisher's version ) (Closed access), DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

Published
2017

30. The first Scube3 mutant mouse line with pleiotropic phenotypic alterations

Author

Fuchs, H., Sabrautzki, S., Przemeck, G.K.H., Leuchtenberger, S., Lorenz-Depiereux, B., Becker, L., Rathkolb, B., Horsch, M., Garrett, L., Östereicher, M.A., Hans, W., Abe, K., Sagawa, N., Rozman, J., Vargas Panesso, I.L., Sandholzer, M., Lisse, T.S., Adler, T., Aguilar-Pimentel, J.A., Calzada-Wack, J., Ehrhard, N., Elvert, R., Gau, C., Hölter, S.M., Micklich, K., Moreth, K., Prehn, C., Puk, O., Rácz, I., Stöger, C., Vernaleken, A., Michel, D., Diener, S., Wieland, T., Adamski, J., Bekeredjian, R., Lengger, C., Maier, H., Neff, F., Ollert, M., Stöger, T., Yildirim, A.Ö., Strom, T.M., Zimmer, A., Wolf, E., Wurst, W., Klopstock, T., Beckers, J., Gailus-Durner, V., and Hrabě de Angelis, M.

Subjects
SCUBE3, Paget disease of bone (PDB), mouse model, pleiotropy, systemic phenotype
Abstract

The vertebrate Scube (Signal peptide, CUB and EGF-like domain-containing protein) family consists of three independent members Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3N294K/N294K) that clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to understand SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3. In addition, alterations in energy metabolism, behavior and neurological functions were detected in Scube3N294K/N294K mice. The Scube3N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Published
2016

31. Molecular genetic analysis of retinitis pigmentosa in Indonesia using genome-wide homozygosity mapping

Author

Siemiatkowska, A.M., Arimadyo, K., Moruz, L.M., Astuti, G.D., de Castro-Miró, M., Zonneveld, M.N., Strom, T.M., de Wijs, I.J., Hoefsloot, L.H., Faradz, S.M., Cremers, F.P., den Hollander, A.I., and Collin, R.W.

Subjects
Adult, Male, Genetics and epigenetic pathways of disease [NCMLS 6], Adolescent, DNA Mutational Analysis, Molecular Sequence Data, Genes, Recessive, Polymorphism, Single Nucleotide, Proto-Oncogene Mas, Genomic disorders and inherited multi-system disorders [IGMD 3], Cohort Studies, Asian People, Genes, X-Linked, Electroretinography, Humans, Genetic Testing, Lebers congenital amaurosis, Ligand-binding domain, Nuclear receptor, Missense mutations, Crystal-structure, Linkage Analyses, Acid, identification, Dystrophy, ABCR, Child, Eye Proteins, Aged, Genome, Human, Homozygote, Chromosome Mapping, Middle Aged, eye diseases, Pedigree, Indonesia, Mutation, Female, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], Retinitis Pigmentosa, Research Article, Genome-Wide Association Study
Abstract

Contains fulltext : 98108.pdf (Publisher’s version ) (Open Access) PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous retinal disorder. Despite tremendous knowledge about the genes involved in RP, little is known about the genetic causes of RP in Indonesia. Here, we aim to identify the molecular genetic causes underlying RP in a small cohort of Indonesian patients, using genome-wide homozygosity mapping. METHODS: DNA samples from affected and healthy individuals from 14 Indonesian families segregating autosomal recessive, X-linked, or isolated RP were collected. Homozygosity mapping was conducted using Illumina 6k or Affymetrix 5.0 single nucleotide polymorphism (SNP) arrays. Known autosomal recessive RP (arRP) genes residing in homozygous regions and X-linked RP genes were sequenced for mutations. RESULTS: In ten out of the 14 families, homozygous regions were identified that contained genes known to be involved in the pathogenesis of RP. Sequence analysis of these genes revealed seven novel homozygous mutations in ATP-binding cassette, sub-family A, member 4 (ABCA4), crumbs homolog 1 (CRB1), eyes shut homolog (Drosophila) (EYS), c-mer proto-oncogene tyrosine kinase (MERTK), nuclear receptor subfamily 2, group E, member 3 (NR2E3) and phosphodiesterase 6A, cGMP-specific, rod, alpha (PDE6A), all segregating in the respective families. No mutations were identified in the X-linked genes retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (X-linked recessive; RP2). CONCLUSIONS: Homozygosity mapping is a powerful tool to identify the genetic defects underlying RP in the Indonesian population. Compared to studies involving patients from other populations, the same genes appear to be implicated in the etiology of recessive RP in Indonesia, although all mutations that were discovered are novel and as such may be unique for this population.

Published
2011

32. Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I

Author

Braunisch, M.C., primary, Gallwitz, H., additional, Abicht, A., additional, Diebold, I., additional, Holinski-Feder, E., additional, Van Maldergem, L., additional, Lammens, M., additional, Kovács-Nagy, R., additional, Alhaddad, B., additional, Strom, T.M., additional, Meitinger, T., additional, Senderek, J., additional, Rudnik-Schöneborn, S., additional, and Haack, T.B., additional

Published
2017
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36. The Power of Gene-Based Rare Variant Methods to Detect Disease-Associated Variation and Test Hypotheses About Complex Disease

Author

Moutsianas, L., Agarwala, V., Fuchsberger, C., Flannick, J., Rivas, M.A., Gaulton, K.J., Albers, P.K., GoT2D Consortium (McCarthy, M.I., Gieger, C., Grallert, H., Hrabě de Angelis, M., Huth, C., Kriebel, J., Meisinger, C., Meitinger, T., Müller-Nurasyid, M., Peters, A., Ried, J.S., Strauch, K., Strom, T.M.), McVean, G., Boehnke, M., and Altshuler, D.

Subjects
Phenotype, Diabetes Mellitus, Type 2, Genetic Diseases, Inborn, Genetic Variation, Humans, Computer Simulation, Exome, Genetic Predisposition to Disease, Models, Theoretical, Alleles, Linkage Disequilibrium, Research Article, Genome-Wide Association Study
Abstract

Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a) generate sequence variation at human genes in up to 10K case-control samples, and (b) quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α=2.5×10-6) in 3K individuals; even in 10K samples, power is modest (~60%). The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci., Author Summary Re-sequencing technologies allow for a more complete interrogation of the role of human variation in complex disease. The inadequate power of single variant methods to assess the role of less common variation has led to the development of numerous statistical methods for testing aggregate groups of variants for association with disease. Such endeavors pose substantial analytical challenges, however, due to the diverse array of genetic hypotheses that need to be considered. In this work, we systematically quantify and compare the performance of a panel of commonly used gene-based association methods under a range of allelic architectures, significance thresholds, locus effect sizes, sample sizes, and filters for neutral variation. We find that MiST, SKAT-O, and KBAC have the highest mean power across simulated datasets. Across all methods, however, the power to detect even loci of relatively large effect is very low at exome-wide significance thresholds for sample sizes comparable with those of ongoing sequencing studies; as such, the absence of signal in studies of a few thousand individuals does not exclude a role for rare variation in complex traits. Finally, we directly compare the results reported by different gene-based methods in order to identify their comparative advantages and disadvantages under distinct locus architectures. Our findings have implications for meaningful interpretation of both positive and negative findings in ongoing and future sequencing studies.

Published
2015

37. Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Author

Mahajan, A., Sim, X., Ng, H.J., Manning, A., Rivas, M.A., Highland, H.M., Locke, A.E., Grarup, N., Im, H.K., Cingolani, P., Flannick, J., Fontanillas, P., Fuchsberger, C., Gaulton, K.J., Teslovich, T.M., Rayner, N.W., Robertson, N.R., Beer, N.L., Rundle, J.K., Bork-Jensen, J., Ladenvall, C., Blancher, C., Buck, D., Buck, G., Burtt, N.P., Gabriel, S., Gjesing, A.P., Groves, C.J., Hollensted, M., Huyghe, J.R., Jackson, A.U., Jun, G., Justesen, J.M., Mangino, M., Murphy, J., Neville, M., Onofrio, R., Small, K.S., Stringham, H.M., Syvanen, A.C., Trakalo, J., Abecasis, G., Bell, G.I., Blangero, J., Cox, N.J., Duggirala, R., Hanis, C.L., Seielstad, M., Wilson, J.G., Christensen, C., Brandslund, I., Rauramaa, R., Surdulescu, G.L., Doney, A.S., Lannfelt, L., Linneberg, A., Isomaa, B., Tuomi, T., Jørgensen, M.E., Jørgensen, T., Kuusisto, J., Uusitupa, M., Salomaa, V., Spector, T.D., Morris, A.D., Palmer, C.N., Collins, F.S., Mohlke, K.L., Bergman, R.N., Ingelsson, E., Lind, L., Tuomilehto, J., Hansen, T., Watanabe, R.M., Prokopenko, I., Dupuis, J., Karpe, F., Groop, L., Laakso, M., Pedersen, O., Florez, J.C, Morris, A.P., Altshuler, D., Meigs, J.B., Boehnke, M., McCarthy, M.I., Lindgren, C.M., Gloyn, A.L., T2D-GENES Consortium (), GoT2D Consortium (Hrabě de Angelis, M., Gieger, C., Grallert, H., Huth, C., Kriebel, J., Meisinger, C., Meitinger, T., Müller-Nurasyid, M., Peters, A., Ried, J.S., Strauch, K., and Strom, T.M.)

Subjects
Blood Glucose, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2, Gene Frequency, Glycemic Index, Glucose-6-Phosphatase, Receptors, Glucagon, Humans, Insulin, Exome, Medical Genetics, Research Article, Genome-Wide Association Study, Medicinsk genetik
Abstract

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P, Author Summary Understanding how FI and FG levels are regulated is important because their derangement is a feature of T2D. Despite recent success from GWAS in identifying regions of the genome influencing glycemic traits, collectively these loci explain only a small proportion of trait variance. Unlocking the biological mechanisms driving these associations has been challenging because the vast majority of variants map to non-coding sequence, and the genes through which they exert their impact are largely unknown. In the current study, we sought to increase our understanding of the physiological pathways influencing both traits using exome-array genotyping in up to 33,231 non-diabetic individuals to identify coding variants and consequently genes associated with either FG or FI levels. We identified novel association signals for both traits including the receptor for GLP-1 agonists which are a widely used therapy for T2D. Furthermore, we identified coding variants at several GWAS loci which point to the genes underlying these association signals. Importantly, we found that multiple coding variants in G6PC2 result in a loss of protein function and lower fasting glucose levels.

Published
2015

40. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., Ahn, E.Y., Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., and Ahn, E.Y.

Abstract

Item does not contain fulltext, The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Published
2016

41. Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2

Author

Kennedy, H., Haack, T.B., Hartill, V., Matakovic, L., Baumgartner, E.R., Potter, H., Mackay, R., Alston, C.L., O'Sullivan, S., McFarland, R., Connolly, G., Gannon, C., King, R., Mead, S., Crozier, I., Chan, W., Florkowski, C.M., Sage, M., Hofken, T., Alhaddad, B., Kremer, L.S., Kopajtich, R., Feichtinger, R.G., Sperl, W., Rodenburg, R.J.T., Minet, J.C., Dobbie, A., Strom, T.M., Meitinger, T., George, P.M., Johnson, C.A., Taylor, R.W., Prokisch, H., Doudney, K., Mayr, J.A., Kennedy, H., Haack, T.B., Hartill, V., Matakovic, L., Baumgartner, E.R., Potter, H., Mackay, R., Alston, C.L., O'Sullivan, S., McFarland, R., Connolly, G., Gannon, C., King, R., Mead, S., Crozier, I., Chan, W., Florkowski, C.M., Sage, M., Hofken, T., Alhaddad, B., Kremer, L.S., Kopajtich, R., Feichtinger, R.G., Sperl, W., Rodenburg, R.J.T., Minet, J.C., Dobbie, A., Strom, T.M., Meitinger, T., George, P.M., Johnson, C.A., Taylor, R.W., Prokisch, H., Doudney, K., and Mayr, J.A.

Abstract

Contains fulltext : 171563.pdf (Publisher’s version ) (Open Access), We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Published
2016

42. Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-Linked Kabuki Syndrome subtype 2

Author

Bögershausen, N., Gatinois, V., Riehmer, V., Kayserili, H., Becker, J., Thoenes, M., Simsek-Kiper, P.Ö., Barat-Houari, M., Elcioglu, N.H., Wieczorek, D., Tinschert, S., Sarrabay, G., Strom, T.M., Fabre, A., Baynam, G., Sanchez, E., Nürnberg, G., Altunoglu, U., Capri, Y., Isidor, B., Lacombe, D., Corsini, C., Cormier-Daire, V., Sanlaville, D., Giuliano, F., Le Quan Sang, K-H, Kayirangwa, H., Nürnberg, P., Meitinger, T., Boduroglu, K., Zoll, B., Lyonnet, S., Tzschach, A., Verloes, A., Di Donato, N., Touitou, I., Netzer, C., Li, Y., Geneviève, D., Yigit, G., Wollnik, B., Bögershausen, N., Gatinois, V., Riehmer, V., Kayserili, H., Becker, J., Thoenes, M., Simsek-Kiper, P.Ö., Barat-Houari, M., Elcioglu, N.H., Wieczorek, D., Tinschert, S., Sarrabay, G., Strom, T.M., Fabre, A., Baynam, G., Sanchez, E., Nürnberg, G., Altunoglu, U., Capri, Y., Isidor, B., Lacombe, D., Corsini, C., Cormier-Daire, V., Sanlaville, D., Giuliano, F., Le Quan Sang, K-H, Kayirangwa, H., Nürnberg, P., Meitinger, T., Boduroglu, K., Zoll, B., Lyonnet, S., Tzschach, A., Verloes, A., Di Donato, N., Touitou, I., Netzer, C., Li, Y., Geneviève, D., Yigit, G., and Wollnik, B.

Abstract

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype–genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.

Published
2016

43. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., Ahn, E.-Y.E. (Eun-Young Erin), Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., and Ahn, E.-Y.E. (Eun-Young Erin)

Abstract

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses c

Published
2016
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44. Mutations in the gene for epsilon-sarcoglycan (SGCE) cause myoclonus-dystonia syndrome

Author

Grabowski, M., Zimprich, A., Asmus, F, Bauer, M., Naumann, M., Berg, D., Bertram, M., Winkelmann, J, Muller-Myhsok, B., Meitinger, T., Strom, T.M., and Gasser, T.

Subjects
Human genetics -- Research, Gene mutations -- Physiological aspects, Myoclonus -- Genetic aspects, Diseases -- Genetic aspects, Biological sciences
Published
2001

46. A powerful tool for genome analysis in maize: Development and evaluation of the high density 600k SNP genotyping array

Author

Unterseer, S., Bauer, E., Haberer, G., Seidel, M., Knaak, C., Ouzunova, M., Meitinger, T., Strom, T.M., Fries, R., Pausch, H., Bertani, C., Davassi, A., Mayer, K.F.X., and Schön, C.C.

Subjects
High Density Genotyping Array, Maize, Snp
Abstract

Background High density genotyping data are indispensable for genomic analyses of complex traits in animal and crop species. Maize is one of the most important crop plants worldwide, however a high density SNP genotyping array for analysis of its large and highly dynamic genome was not available so far. Results We developed a high density maize SNP array composed of 616,201 variants (SNPs and small indels). Initially, 57 M variants were discovered by sequencing 30 representative temperate maize lines and then stringently filtered for sequence quality scores and predicted conversion performance on the array resulting in the selection of 1.2 M polymorphic variants assayed on two screening arrays. To identify high-confidence variants, 285 DNA samples from a broad genetic diversity panel of worldwide maize lines including the samples used for sequencing, important founder lines for European maize breeding, hybrids, and proprietary samples with European, US, semi-tropical, and tropical origin were used for experimental validation. We selected 616 k variants according to their performance during validation, support of genotype calls through sequencing data, and physical distribution for further analysis and for the design of the commercially available Affymetrix(R) Axiom(R) Maize Genotyping Array. This array is composed of 609,442 SNPs and 6,759 indels. Among these are 116,224 variants in coding regions and 45,655 SNPs of the Illumina(R) MaizeSNP50 BeadChip for study comparison. In a subset of 45,974 variants, apart from the target SNP additional off-target variants are detected, which show only a minor bias towards intermediate allele frequencies. We performed principal coordinate and admixture analyses to determine the ability of the array to detect and resolve population structure and investigated the extent of LD within a worldwide validation panel. Conclusions The high density Affymetrix(R) Axiom(R) Maize Genotyping Array is optimized for European and American temperate maize and was developed based on a diverse sample panel by applying stringent quality filter criteria to ensure its suitability for a broad range of applications. With 600 k variants it is the largest currently publically available genotyping array in crop species.

Published
2014

47. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome

Author

Beuschlein, F., Fassnacht, M., Assié, G., Calebiro, D., Stratakis, C.A., Osswald, A., Ronchi, C.L., Wieland, T., Sbiera, S., Faucz, F.R., Schaak, K., Schmittfull, A., Schwarzmayr, T., Barreau, O., Vezzosi, D., Rizk-Rabin, M., Zabel, U., Szarek, E., Salpea, P., Forlino, A., Vetro, A., Zuffardi, O., Kisker, C., Diener, S., Meitinger, T., Lohse, M.J., Reincke, M., Bertherat, J., Strom, T.M., and Allolio, B.

Abstract

Background Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. Methods We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. Results Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. Conclusions Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).

Published
2014

49. Expanding the clinical spectrum of the ‘HDAC8-phenotype’ - implications for molecular diagnostics, counseling and risk prediction

Author

Parenti, I., primary, Gervasini, C., additional, Pozojevic, J., additional, Wendt, K.S., additional, Watrin, E., additional, Azzollini, J., additional, Braunholz, D., additional, Buiting, K., additional, Cereda, A., additional, Engels, H., additional, Garavelli, L., additional, Glazar, R., additional, Graffmann, B., additional, Larizza, L., additional, Lüdecke, H.J., additional, Mariani, M., additional, Masciadri, M., additional, Pié, J., additional, Ramos, F.J., additional, Russo, S., additional, Selicorni, A., additional, Stefanova, M., additional, Strom, T.M., additional, Werner, R., additional, Wierzba, J., additional, Zampino, G., additional, Gillessen-Kaesbach, G., additional, Wieczorek, D., additional, and Kaiser, F.J., additional

Published
2016
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50. MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy

Author

Distelmaier, F., Haack, T.B., Catarino, C.B., Gallenmuller, C., Rodenburg, R.J.T., Strom, T.M., Baertling, F., Meitinger, T., Mayatepek, E., Prokisch, H., Klopstock, T., Distelmaier, F., Haack, T.B., Catarino, C.B., Gallenmuller, C., Rodenburg, R.J.T., Strom, T.M., Baertling, F., Meitinger, T., Mayatepek, E., Prokisch, H., and Klopstock, T.

Abstract

Item does not contain fulltext, Defects in mitochondrial translation may lead to combined respiratory chain deficiency and typically cause childhood-onset multisystem disease. Only recently, a homozygous missense mutation (c.467T > G, p.Leu156Arg) in MRPL44, encoding a protein of the large subunit of the mitochondrial ribosome, has been identified in two siblings with hypertrophic cardiomyopathy. Using exome sequencing, we identified two further unrelated patients harboring the previously reported mutation c.467T > G, p.Leu156Arg in MRPL44 in the homozygous state and compound heterozygous with a novel missense mutation c.233G > A, p.Arg78Gln, respectively. Both patients presented with childhood-onset hypertrophic cardiomyopathy, which seems to be the core clinical feature associated with MRPL44 deficiency. However, we observed several additional clinical signs and symptoms including pigmentary retinopathy, hemiplegic migraine, Leigh-like lesions on brain MRI, renal insufficiency, and hepatopathy. Our findings expand the clinical spectrum associated with MRPL44 mutations and indicate that MRPL44-associated mitochondrial dysfunction can also manifest as a progressive multisystem disease with central nervous system involvement. Of note, neurological and neuro-ophthalmological impairment seems to be a disease feature of the second and third decades of life, which should be taken into account in patient management and counseling.

Published
2015

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