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1. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author

Stegmann, Jil D., Kalanithy, Jeshurun C., Dworschak, Gabriel C., Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M., Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T., Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J., Klee, Eric W., Lanpher, Brendan C., Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R., Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L., Riley, Kacie, Klee, Victoria, Walsh, Laurence E., Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stoppe, Arzu, Stuurman, Kyra, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Mulhern, Maureen S., Sands, Tristan T., Cytrynbaum, Cheryl, Weksberg, Rosanna, Isidori, Federica, Pippucci, Tommaso, Severi, Giulia, Montanari, Francesca, Kruer, Michael C., Bakhtiari, Somayeh, Darvish, Hossein, Reutter, Heiko, Hagelueken, Gregor, Geyer, Matthias, Woolf, Adrian S., Posey, Jennifer E., Lupski, James R., Odermatt, Benjamin, and Hilger, Alina C.

Published
2024
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2. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Published
2023
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3. Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1

Author

Patterson, Karynne, Chong, Jessica X., Chung, Doug D., Lisch, Walter, Karp, Carol L., Dreisler, Erling, Lockington, David, Rohrbach, Jens M., Garczarczyk-Asim, Dorota, Müller, Thomas, Tuft, Stephen J., Skalicka, Pavlina, Wilnai, Yael, Samra, Nadra Naser, Ibrahim, Ali, Mandel, Hanna, Davidson, Alice E., Liskova, Petra, Aldave, Anthony J., Bamshad, Michael J., and Janecke, Andreas R.

Published
2024
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4. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Author

Wiessner, Manuela, Maroofian, Reza, Ni, Meng-Yuan, Pedroni, Andrea, Müller, Juliane S, Stucka, Rolf, Beetz, Christian, Efthymiou, Stephanie, Santorelli, Filippo M, Alfares, Ahmed A, Zhu, Changlian, Uhrova Meszarosova, Anna, Alehabib, Elham, Bakhtiari, Somayeh, Janecke, Andreas R, Otero, Maria Gabriela, Chen, Jin Yun Helen, Peterson, James T, Strom, Tim M, De Jonghe, Peter, Deconinck, Tine, De Ridder, Willem, De Winter, Jonathan, Pasquariello, Rossella, Ricca, Ivana, Alfadhel, Majid, van de Warrenburg, Bart P, Portier, Ruben, Bergmann, Carsten, Ghasemi Firouzabadi, Saghar, Jin, Sheng Chih, Bilguvar, Kaya, Hamed, Sherifa, Abdelhameed, Mohammed, Haridy, Nourelhoda A, Maqbool, Shazia, Rahman, Fatima, Anwar, Najwa, Carmichael, Jenny, Pagnamenta, Alistair, Wood, Nick W, Tran Mau-Them, Frederic, Haack, Tobias, Di Rocco, Maja, Ceccherini, Isabella, Iacomino, Michele, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Rusmini, Marta, Xu, Yiran, Wang, Yinghong, Suzuki, Yasuhiro, Koh, Kishin, Nan, Haitian, Ishiura, Hiroyuki, Tsuji, Shoji, Lambert, Laëtitia, Schmitt, Emmanuelle, Lacaze, Elodie, Küpper, Hanna, Dredge, David, Skraban, Cara, Goldstein, Amy, Willis, Mary JH, Grand, Katheryn, Graham, John M, Lewis, Richard A, Millan, Francisca, Duman, Özgür, Dündar, Nihal, Uyanik, Gökhan, Schöls, Ludger, Nürnberg, Peter, Nürnberg, Gudrun, Catala Bordes, Andrea, Seeman, Pavel, Kuchar, Martin, Darvish, Hossein, Rebelo, Adriana, Bouçanova, Filipa, Medard, Jean-Jacques, Chrast, Roman, Auer-Grumbach, Michaela, Alkuraya, Fowzan S, Shamseldin, Hanan, Al Tala, Saeed, Rezazadeh Varaghchi, Jamileh, Najafi, Maryam, Deschner, Selina, Gläser, Dieter, Hüttel, Wolfgang, Kruer, Michael C, Kamsteeg, Erik-Jan, Takiyama, Yoshihisa, Züchner, Stephan, Baets, Jonathan, Synofzik, Matthis, Schüle, Rebecca, and Horvath, Rita

Subjects
Neurosciences, Neurodegenerative, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Female, Humans, Male, Mice, Mutation, Oxygenases, Pedigree, Rats, Spastic Paraplegia, Hereditary, Zebrafish, hereditary spastic paraplegia, HSP, autosomal recessive, mitochondrial disorder, HPDL, Genomics England Research Consortium, PREPARE network, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

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

5. Kinesin family member 12‐related hepatopathy: A generally indolent disorder with elevated gamma‐glutamyl‐transferase activity.

Author

Vogel, Georg‐Friedrich, Podpeskar, Alexandra, Rieder, Dietmar, Salzer, Helin, Garczarczyk‐Asim, Dorota, Wang, Li, Abuduxikuer, Kuerbanjiang, Wang, Jian‐She, Scharrer, Anke, Faqeih, Eissa Ali, Aseeri, Ali T., Vodopiutz, Julia, Heilos, Andreas, Pichler, Judith, Huber, Wolf‐Dietrich, Müller, Thomas, Knisely, A. S., and Janecke, Andreas R.

Subjects
HEPATIC fibrosis, LIVER failure, CHILD patients, LIVER transplantation, LIVER diseases, GAMMA-glutamyltransferase
Abstract

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma‐glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12‐related disease from other entities with elevated GGT. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author

Stegmann, Jil D, Kalanithy, Jeshurun C, Dworschak, Gabriel C, Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M, Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T, Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J, Klee, Eric W, Lanpher, Brendan C, Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R, Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L, Riley, Kacie, Klee, Victoria, Walsh, Laurence E, Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stuurman, Kyra, van Slegtenhorst, Marjon, Stegmann, Jil D, Kalanithy, Jeshurun C, Dworschak, Gabriel C, Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M, Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T, Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J, Klee, Eric W, Lanpher, Brendan C, Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R, Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L, Riley, Kacie, Klee, Victoria, Walsh, Laurence E, Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stuurman, Kyra, and van Slegtenhorst, Marjon

Abstract

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Published
2024

7. The phenotype of the musculocontractural type of Ehlers‐Danlos syndrome due to CHST14 mutations

Author

Janecke, Andreas R, Li, Ben, Boehm, Manfred, Krabichler, Birgit, Rohrbach, Marianne, Müller, Thomas, Fuchs, Irene, Golas, Gretchen, Katagiri, Yasuhiro, Ziegler, Shira G, Gahl, William A, Wilnai, Yael, Zoppi, Nicoletta, Geller, Herbert M, Giunta, Cecilia, Slavotinek, Anne, and Steinmann, Beat

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Rare Diseases, Brain Disorders, Clinical Research, Pediatric, Adolescent, Adult, Child, Child, Preschool, Connective Tissue Diseases, Dermis, Ehlers-Danlos Syndrome, Female, Fibroblasts, Fluorescent Antibody Technique, Indirect, Humans, Infant, Male, Middle Aged, Mutation, Sulfotransferases, Young Adult, dermatan sulfate, deficiency, dermatan sulfate epimerase, N-acetylgalactosamine 4-O-sulfotransferase, connective tissue, Ehlers-Danlos syndrome, adducted thumb, clubfoot, proteoglycan, arthrogryposis, myopathy, Genetics, Clinical Sciences, Clinical sciences
Abstract

The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.

Published
2016

11. UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking

Author

Duclaux-Loras, Remi, Lebreton, Corinne, Berthelet, Jeremy, Charbit-Henrion, Fabienne, Nicolle, Ophelie, de Courtils, Celine Revenu, Waich, Stephanie, Valovka, Taras, Khiat, Anis, Rabant, Marion, Racine, Caroline, Guerrera, Ida Chiara, Baptista, Julia, Mahe, Maxime M., Hess, Michael W., Durel, Beatrice, Lefort, Nathalie, Banal, Celine, Parisot, Melanie, Talbotec, Cecile, Lacaille, Florence, Ecochard-Dugelay, Emmanuelle, Demir, Arzu Meltem, Vogel, Georg F., Faivre, Laurence, Rodrigues, Astor, Fowler, Darren, Janecke, Andreas R., Muller, Thomas, Huber, Lukas A., Rodrigues-Lima, Fernando, Ruemmele, Frank M., Uhlig, Holm H., Del Bene, Filippo, Michaux, Gregoire, Cerf-Bensussan, Nadine, and Parlato, Marianna

Subjects
Gene mutations -- Research, Genetic disorders -- Causes of, Medical research, Medicine, Experimental, Myosin -- Genetic aspects -- Health aspects, Diarrhea -- Genetic aspects -- Causes of, Molecular chaperones -- Genetic aspects -- Health aspects, Cell membranes -- Health aspects, Phenotype -- Research, Health care industry
Abstract

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in [UNC45A.sup.KO] Caco-2 cells. In keeping with impaired myosin VB function, [UNC45A.sup.KO] Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and [UNC45A.sup.KO] 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease., Introduction Congenital diarrhea disorders (CDDs) are rare monogenic diseases characterized by chronic, life-threatening diarrhea starting early in life (1, 2). Depending on the mechanism, diarrhea can be the only symptom [...]

Published
2022
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12. Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency

Author

van Rijn, Jorik M., Ardy, Rico Chandra, Kuloğlu, Zarife, Härter, Bettina, van Haaften-Visser, Désirée Y., van der Doef, Hubert P.J., van Hoesel, Marliek, Kansu, Aydan, van Vugt, Anke H.M., Thian, Marini, Kokke, Freddy T.M., Krolo, Ana, Başaran, Meryem Keçeli, Kaya, Neslihan Gurcan, Aksu, Aysel Ünlüsoy, Dalgıç, Buket, Ozcay, Figen, Baris, Zeren, Kain, Renate, Stigter, Edwin C.A., Lichtenbelt, Klaske D., Massink, Maarten P.G., Duran, Karen J., Verheij, Joke B.G.M, Lugtenberg, Dorien, Nikkels, Peter G.J., Brouwer, Henricus G.F., Verkade, Henkjan J., Scheenstra, René, Spee, Bart, Nieuwenhuis, Edward E.S., Coffer, Paul J., Janecke, Andreas R., van Haaften, Gijs, Houwen, Roderick H.J., Müller, Thomas, Middendorp, Sabine, and Boztug, Kaan

Published
2018
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13. Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Author

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R, McInerney-Leo, Aideen M, Emes, Richard D, Arts, Heleen H, Tüysüz, Beyhan, D’Silva, Jason, Leo, Paul J, Giles, Tom C, Oud, Machteld M, Harris, Jessica A, Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T, Wilson, Louise C, Janecke, Andreas R, Hurles, Matthew E, Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J, Brown, Matthew A, Beales, Philip L, Wicking, Carol, UK10K, Duncan, Emma L, and Mitchison, Hannah M

Subjects
Rare Diseases, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Asians, Axoneme, Carrier Proteins, Child, Chlamydomonas, Cilia, Cytoplasmic Dyneins, Cytoskeleton, Ellis-Van Creveld Syndrome, Exome, Exons, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Mutation, Protein Conformation, Proteomics, Whites, UK10K, Asian People, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Published
2013

14. Author Correction: Mutations in PYCR1 cause cutis laxa with progeroid features

Author

Reversade, Bruno, Escande-Beillard, Nathalie, Dimopoulou, Aikaterini, Fischer, Björn, Chng, Serene C., Li, Yun, Shboul, Mohammad, Tham, Puay-Yoke, Kayserili, Hülya, Al-Gazali, Lihadh, Shahwan, Monzer, Brancati, Francesco, Lee, Hane, O’Connor, Brian D., Kegler, Mareen Schmidt-von, Merriman, Barry, Nelson, Stanley F., Masri, Amira, Alkazaleh, Fawaz, Guerra, Deanna, Ferrari, Paola, Nanda, Arti, Rajab, Anna, Markie, David, Gray, Mary, Nelson, John, Grix, Arthur, Sommer, Annemarie, Savarirayan, Ravi, Janecke, Andreas R., Steichen, Elisabeth, Sillence, David, Haußer, Ingrid, Budde, Birgit, Nürnberg, Gudrun, Nürnberg, Peter, Seemann, Petra, Kunkel, Désirée, Zambruno, Giovanna, Dallapiccola, Bruno, Schuelke, Markus, Robertson, Stephen, Hamamy, Hanan, Wollnik, Bernd, Van Maldergem, Lionel, Mundlos, Stefan, and Kornak, Uwe

Published
2022
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16. Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

Author

Gruber, Robert, Rogerson, Clare, Windpassinger, Christian, Banushi, Blerida, Straatman-Iwanowska, Anna, Hanley, Joanna, Forneris, Federico, Strohal, Robert, Ulz, Peter, Crumrine, Debra, Menon, Gopinathan K., Blunder, Stefan, Schmuth, Matthias, Müller, Thomas, Smith, Holly, Mills, Kevin, Kroisel, Peter, Janecke, Andreas R., and Gissen, Paul

Published
2017
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18. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

19. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

23. Internal Ileal Diversion as Treatment for Progressive Familial Intrahepatic Cholestasis Type 1-Associated Graft Inflammation and Steatosis after Liver Transplantation

Author

Kavallar, Anna M., primary, Messner, Franka, additional, Scheidl, Stefan, additional, Oberhuber, Rupert, additional, Schneeberger, Stefan, additional, Aldrian, Denise, additional, Berchtold, Valeria, additional, Sanal, Murat, additional, Entenmann, Andreas, additional, Straub, Simon, additional, Gasser, Anna, additional, Janecke, Andreas R., additional, Müller, Thomas, additional, and Vogel, Georg F., additional

Published
2022
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28. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Author

Solaki, Maria, Baumann, Britta, Reuter, Peggy, Andreasson, Sten, Audo, Isabelle, Ayuso, Carmen, Balousha, Ghassan, Benedicenti, Francesco, Birch, David, Bitoun, Pierre, Blain, Delphine, Bocquet, Beatrice, Branham, Kari, Català-Mora, Jaume, De Baere, Elfride, Dollfus, Helene, Falana, Mohammed, Giorda, Roberto, Golovleva, Irina, Gottlob, Irene, Heckenlively, John R., Jacobson, Samuel G., Jones, Kaylie, Jägle, Herbert, Janecke, Andreas R., Kellner, Ulrich, Liskova, Petra, Lorenz, Birgit, Martorell-Sampol, Loreto, Messias, André, Meunier, Isabelle, Belga Ottoni Porto, Fernanda, Papageorgiou, Eleni, Plomp, Astrid S., de Ravel, Thomy J. L., Reiff, Charlotte M., Renner, Agnes B., Rosenberg, Thomas, Rudolph, Günther, Salati, Roberto, Sener, E. Cumhur, Sieving, Paul A., Stanzial, Franco, Traboulsi, Elias I., Tsang, Stephen H., Varsanyi, Balázs, Weleber, Richard G., Zobor, Ditta, Stingl, Katarina, Wissinger, Bernd, Kohl, Susanne, Solaki, Maria, Baumann, Britta, Reuter, Peggy, Andreasson, Sten, Audo, Isabelle, Ayuso, Carmen, Balousha, Ghassan, Benedicenti, Francesco, Birch, David, Bitoun, Pierre, Blain, Delphine, Bocquet, Beatrice, Branham, Kari, Català-Mora, Jaume, De Baere, Elfride, Dollfus, Helene, Falana, Mohammed, Giorda, Roberto, Golovleva, Irina, Gottlob, Irene, Heckenlively, John R., Jacobson, Samuel G., Jones, Kaylie, Jägle, Herbert, Janecke, Andreas R., Kellner, Ulrich, Liskova, Petra, Lorenz, Birgit, Martorell-Sampol, Loreto, Messias, André, Meunier, Isabelle, Belga Ottoni Porto, Fernanda, Papageorgiou, Eleni, Plomp, Astrid S., de Ravel, Thomy J. L., Reiff, Charlotte M., Renner, Agnes B., Rosenberg, Thomas, Rudolph, Günther, Salati, Roberto, Sener, E. Cumhur, Sieving, Paul A., Stanzial, Franco, Traboulsi, Elias I., Tsang, Stephen H., Varsanyi, Balázs, Weleber, Richard G., Zobor, Ditta, Stingl, Katarina, Wissinger, Bernd, and Kohl, Susanne

Abstract

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease-causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease-causing” according to ACMG/AMP criteria. We report 48 novel “likely disease-causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Published
2022
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29. Chondroitin Sulfate N‐acetylgalactosaminyltransferase‐1 (CSGalNAcT‐1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity

Author

Vodopiutz, Julia, Mizumoto, Shuji, Lausch, Ekkehart, Rossi, Antonio, Unger, Sheila, Janocha, Nikolaus, Costantini, Rossella, Seidl, Rainer, Greber‐Platzer, Susanne, Yamada, Shuhei, Müller, Thomas, Jilma, Bernd, Ganger, Rudolf, Superti‐Furga, Andrea, Ikegawa, Shiro, Sugahara, Kazuyuki, and Janecke, Andreas R.

Published
2017
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31. Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

Author

Romani, Marta, Mancini, Francesca, Micalizzi, Alessia, Poretti, Andrea, Miccinilli, Elide, Accorsi, Patrizia, Avola, Emanuela, Bertini, Enrico, Borgatti, Renato, Romaniello, Romina, Ceylaner, Serdar, Coppola, Giangennaro, D’Arrigo, Stefano, Giordano, Lucio, Janecke, Andreas R., Lituania, Mario, Ludwig, Kathrin, Martorell, Loreto, Mazza, Tommaso, Odent, Sylvie, Pinelli, Lorenzo, Poo, Pilar, Santucci, Margherita, Signorini, Sabrina, Simonati, Alessandro, Spiegel, Ronen, Stanzial, Franco, Steinlin, Maja, Tabarki, Brahim, Wolf, Nicole I., Zibordi, Federica, Boltshauser, Eugen, and Valente, Enza Maria

Published
2015
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32. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Author

Solaki, Maria, primary, Baumann, Britta, additional, Reuter, Peggy, additional, Andreasson, Sten, additional, Audo, Isabelle, additional, Ayuso, Carmen, additional, Balousha, Ghassan, additional, Benedicenti, Francesco, additional, Birch, David, additional, Bitoun, Pierre, additional, Blain, Delphine, additional, Bocquet, Beatrice, additional, Branham, Kari, additional, Català‐Mora, Jaume, additional, De Baere, Elfride, additional, Dollfus, Helene, additional, Falana, Mohammed, additional, Giorda, Roberto, additional, Golovleva, Irina, additional, Gottlob, Irene, additional, Heckenlively, John R., additional, Jacobson, Samuel G., additional, Jones, Kaylie, additional, Jägle, Herbert, additional, Janecke, Andreas R., additional, Kellner, Ulrich, additional, Liskova, Petra, additional, Lorenz, Birgit, additional, Martorell‐Sampol, Loreto, additional, Messias, André, additional, Meunier, Isabelle, additional, Belga Ottoni Porto, Fernanda, additional, Papageorgiou, Eleni, additional, Plomp, Astrid S., additional, de Ravel, Thomy J. L., additional, Reiff, Charlotte M., additional, Renner, Agnes B., additional, Rosenberg, Thomas, additional, Rudolph, Günther, additional, Salati, Roberto, additional, Sener, E. Cumhur, additional, Sieving, Paul A., additional, Stanzial, Franco, additional, Traboulsi, Elias I., additional, Tsang, Stephen H., additional, Varsanyi, Balázs, additional, Weleber, Richard G., additional, Zobor, Ditta, additional, Stingl, Katarina, additional, Wissinger, Bernd, additional, and Kohl, Susanne, additional

Published
2022
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36. Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form

Author

Salomon, Julie, Goulet, Olivier, Canioni, Danielle, Brousse, Nicole, Lemale, Julie, Tounian, Patrick, Coulomb, Aurore, Marinier, Evelyne, Hugot, Jean-Pierre, Ruemmele, Frank, Dufier, Jean-Louis, Roche, Olivier, Bodemer, Christine, Colomb, Virginie, Talbotec, Cécile, Lacaille, Florence, Campeotto, Florence, Cerf-Bensussan, Nadine, Janecke, Andreas R., Mueller, Thomas, Koletzko, Sibylle, Bonnefont, Jean-Paul, Lyonnet, Stanislas, Munnich, Arnold, Poirier, Françoise, and Smahi, Asma

Published
2014
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38. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea

Author

Janecke, Andreas R., Heinz-Erian, Peter, Yin, Jianyi, Petersen, Britt-Sabina, Franke, Andre, Lechner, Silvia, Fuchs, Irene, Melancon, Serge, Uhlig, Holm H., Travis, Simon, Marinier, Evelyne, Perisic, Vojislav, Ristic, Nina, Gerner, Patrick, Booth, Ian W., Wedenoja, Satu, Baumgartner, Nadja, Vodopiutz, Julia, Frechette-Duval, Marie-Christine, De Lafollie, Jan, Persad, Rabindranath, Warner, Neil, Tse, C. Ming, Sud, Karan, Zachos, Nicholas C., Sarker, Rafiquel, Zhu, Xinjun, Muise, Aleixo M., Zimmer, Klaus-Peter, Witt, Heiko, Zoller, Heinz, Donowitz, Mark, and Müller, Thomas

Published
2015
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39. Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14)

Author

Minatogawa, Mari, primary, Unzaki, Ai, additional, Morisaki, Hiroko, additional, Syx, Delfien, additional, Sonoda, Tohru, additional, Janecke, Andreas R, additional, Slavotinek, Anne, additional, Voermans, Nicol C, additional, Lacassie, Yves, additional, Mendoza-Londono, Roberto, additional, Wierenga, Klaas J, additional, Jayakar, Parul, additional, Gahl, William A, additional, Tifft, Cynthia J, additional, Figuera, Luis E, additional, Hilhorst-Hofstee, Yvonne, additional, Maugeri, Alessandra, additional, Ishikawa, Ken, additional, Kobayashi, Tomoko, additional, Aoki, Yoko, additional, Ohura, Toshihiro, additional, Kawame, Hiroshi, additional, Kono, Michihiro, additional, Mochida, Kosuke, additional, Tokorodani, Chiho, additional, Kikkawa, Kiyoshi, additional, Morisaki, Takayuki, additional, Kobayashi, Tetsuyuki, additional, Nakane, Takaya, additional, Kubo, Akiharu, additional, Ranells, Judith D, additional, Migita, Ohsuke, additional, Sobey, Glenda, additional, Kaur, Anupriya, additional, Ishikawa, Masumi, additional, Yamaguchi, Tomomi, additional, Matsumoto, Naomichi, additional, Malfait, Fransiska, additional, Miyake, Noriko, additional, and Kosho, Tomoki, additional

Published
2021
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43. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Author

Vodopiutz, Julia, Seidl, Rainer, Prayer, Daniela, Khan, Imran M., Mayr, Johannes A., Streubel, Berthold, Stei, Jens-Oliver, Hahn, Andreas, Csaicsich, Dagmar, Castro, Christel, Assoum, Mirna, Müller, Thomas, Wieczorek, Dagmar, Mancini, Grazia M. S., Sadowski, Carolin E., Lévy, Nicolas, Mégarbané, André, Godbole, Koumudi, Schanze, Denny, Hildebrandt, Friedhelm, Delague, Valérie, Janecke, Andreas R., and Zenker, Martin

Published
2015
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44. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies

Author

Safka Brozkova, Dana, Deconinck, Tine, Beth Griffin, Laurie, Ferbert, Andreas, Haberlova, Jana, Mazanec, Radim, Lassuthova, Petra, Roth, Christian, Pilunthanakul, Thanita, Rautenstrauss, Bernd, Janecke, Andreas R., Zavadakova, Petra, Chrast, Roman, Rivolta, Carlo, Zuchner, Stephan, Antonellis, Anthony, Beg, Asim A., De Jonghe, Peter, Senderek, Jan, Seeman, Pavel, and Baets, Jonathan

Published
2015
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45. Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14).

Author

Minatogawa, Mari, Ai Unzaki, Hiroko Morisaki, Syx, Delfien, Tohru Sonoda, Janecke, Andreas R., Slavotinek, Anne, Voermans, Nicol C., Lacassie, Yves, Mendoza-Londono, Roberto, Wierenga, Klaas J., Jayakar, Parul, Gahl, William A., Tifft, Cynthia J., Figuera, Luis E., Hilhorst-Hofstee, Yvonne, Maugeri, Alessandra, Ken Ishikawa, Tomoko Kobayashi, and Yoko Aoki

Abstract

Background Musculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. Methods We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDSCHST14 through international collaborations. Results Sixty-six patients in 48 families (33 males/ females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDSCHST14 than in eight reported patients with mcEDS-DSE. Conclusion This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches. [ABSTRACT FROM AUTHOR]

Published
2022
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47. A Potential Treatment of Congenital Sodium Diarrhea in Patients With Activating GUCY2C Mutations

Author

MDL patientenzorg, Child Health, Regenerative Medicine and Stem Cells, van Vugt, Anke H M, Bijvelds, Marcel J C, de Jonge, Hugo R, Meijsen, Kelly F, Restin, Tanja, Bryant, Manuel B, Ballauff, Antje, Koot, Bart, Müller, Thomas, Houwen, Roderick H J, Janecke, Andreas R, Middendorp, Sabine, MDL patientenzorg, Child Health, Regenerative Medicine and Stem Cells, van Vugt, Anke H M, Bijvelds, Marcel J C, de Jonge, Hugo R, Meijsen, Kelly F, Restin, Tanja, Bryant, Manuel B, Ballauff, Antje, Koot, Bart, Müller, Thomas, Houwen, Roderick H J, Janecke, Andreas R, and Middendorp, Sabine

Published
2021

48. A Potential Treatment of Congenital Sodium Diarrhea in Patients With Activating GUCY2C Mutations

Author

van Vugt, Anke H M, Bijvelds, Marcel J C, de Jonge, Hugo R, Meijsen, Kelly F, Restin, Tanja, Bryant, Manuel B, Ballauff, Antje, Koot, Bart, Müller, Thomas, Houwen, Roderick H J, Janecke, Andreas R; https://orcid.org/0000-0001-7155-0315, Middendorp, Sabine, van Vugt, Anke H M, Bijvelds, Marcel J C, de Jonge, Hugo R, Meijsen, Kelly F, Restin, Tanja, Bryant, Manuel B, Ballauff, Antje, Koot, Bart, Müller, Thomas, Houwen, Roderick H J, Janecke, Andreas R; https://orcid.org/0000-0001-7155-0315, and Middendorp, Sabine

Abstract

INTRODUCTION Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. METHODS We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (cGMP) levels and on GCC-mediated chloride secretion in intestinal organoids from 3 patients with distinct activating GCC mutations and from controls, with and without stimulation of GCC with heat-stable enterotoxin. RESULTS Patient-derived organoids had significantly higher basal cGMP levels than control organoids, which were lowered by SSP2518 to levels found in control organoids. In addition, SSP2518 significantly reduced cGMP levels and chloride secretion in patient-derived and control organoids (P < 0.05 for all comparisons) after heat-stable enterotoxin stimulation. DISCUSSION We reported in this study that the GCC inhibitor SSP2518 normalizes cGMP levels in intestinal organoids derived from patients with GCC gain-of-function mutations and markedly reduces cystic fibrosis transmembrane conductance regulator-dependent chloride secretion, the driver of persistent diarrhea.

Published
2021

49. SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease

Author

Fischer, Carina, Trajanoski, Slave, Papić, Lea, Windpassinger, Christian, Bernert, Günther, Freilinger, Michael, Schabhüttl, Maria, Arslan-Kirchner, Mine, Javaher-Haghighi, Poupak, Plecko, Barbara, Senderek, Jan, Rauscher, Christian, Löscher, Wolfgang N., Pieber, Thomas R., Janecke, Andreas R., and Auer-Grumbach, Michaela

Published
2012
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