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2. Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies

Author

Schueler, Markus, Halbritter, Jan, Phelps, Ian G, Braun, Daniela A, Otto, Edgar A, Porath, Jonathan D, Gee, Heon Yung, Shendure, Jay, OʼRoak, Brian J, Lawson, Jennifer A, Nabhan, Marwa M, Soliman, Neveen A, Doherty, Dan, Hildebrandt, Friedhelm, Yalcinkaya, F, Bakkaloglu, S, Ozaltin, F, Comak, E, Krull, F, Schmitz-Hübner, Rupprecht, H, Muller, D, Dahlem, P, Hoppe, B, Wolfe, M, Weber, M, Vester, U, Bonzel, K, Nikolay, J, Hansmann, I, Wiefel, M, Orth, U, Pfleiderer, H, Pape, L, Morlot, Ehrich, J, Tonshoff, B, Schindera, F, Hoefele, J, Griebel, M, Broeking, E, Konrad, M, Radke, M, Brandis, M, Kirchhoff, A, Feygina, V, Springate, J, Ahmadzdeh, S, Gipson, D, Becker, A, Dharnidharka, V, Mark, P, Srivaths, P, Wilson, A, Kamil, E, Why, S, Pan, C, Kashtan, C, D’Alessandri, C, Trachtman, H, Kaplan, B, Joseph, M, Weiss, R, Thomas, S, Newberry, L, Koyun, M, Fathy, H, RybiSzuminska, A, Szczepanska, M, Dolezel, Z, Malina, M, Seeman, T, Honzik, T, Ferreira, P, Ferguson, M, Harvey, E, Chong, K, Sandford, R, Josifova, D, Bockenhauer, D, Sayer, J, Johnson, C, Senguttuvan, P, Pela, I, Knops, N, Levart, T, Neuhaus, T, Ayuso, C, Kindi, A, Knoers, N, Antignac, C, Radauer, W, Genzani, C, Berg, U, Klingenberg, C, Jones, C, Savarirayan, R, and Kausman, J

Published
2016
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3. Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association

Author

Hilger, Alina C., Halbritter, Jan, Pennimpede, Tracie, van der Ven, Amelie, Sarma, Georgia, Braun, Daniela A., Porath, Jonathan D., Kohl, Stefan, Hwang, Daw-Yang, Dworschak, Gabriel C., Hermann, Bernhard G., Pavlova, Anna, El-Maarri, Osman, Nöthen, Markus M., Ludwig, Michael, Reutter, Heiko, and Hildebrandt, Friedhelm

Published
2015
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4. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Author

Perrault, Isabelle, Halbritter, Jan, Porath, Jonathan D, Gérard, Xavier, Braun, Daniela A, Gee, Heon Yung, Fathy, Hanan M, Saunier, Sophie, Cormier-Daire, Valérie, Thomas, Sophie, Attié-Bitach, Tania, Boddaert, Nathalie, Taschner, Michael, Schueler, Markus, Lorentzen, Esben, Lifton, Richard P, Lawson, Jennifer A, Garfa-Traore, Meriem, Otto, Edgar A, Bastin, Philippe, Caillaud, Catherine, Kaplan, Josseline, Rozet, Jean-Michel, and Hildebrandt, Friedhelm

Published
2015
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11. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Author

Braun, Daniela A., Schueler, Markus, Halbritter, Jan, Gee, Heon Yung, Porath, Jonathan D., Lawson, Jennifer A., Airik, Rannar, Shril, Shirlee, Allen, Susan J., Stein, Deborah, Al Kindy, Adila, Beck, Bodo B., Cengiz, Nurcan, Moorani, Khemchand N., Ozaltin, Fatih, Hashmi, Seema, Sayer, John A., Bockenhauer, Detlef, Soliman, Neveen A., Otto, Edgar A., Lifton, Richard P., Hildebrandt, Friedhelm, Braun, Daniela A., Schueler, Markus, Halbritter, Jan, Gee, Heon Yung, Porath, Jonathan D., Lawson, Jennifer A., Airik, Rannar, Shril, Shirlee, Allen, Susan J., Stein, Deborah, Al Kindy, Adila, Beck, Bodo B., Cengiz, Nurcan, Moorani, Khemchand N., Ozaltin, Fatih, Hashmi, Seema, Sayer, John A., Bockenhauer, Detlef, Soliman, Neveen A., Otto, Edgar A., Lifton, Richard P., and Hildebrandt, Friedhelm

Abstract

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we, performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIASI, INCENP, and RCORI) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

Published
2016

12. SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling

Author

Airik, Rannar, Schueler, Markus, Airik, Merlin, Cho, Jang, Ulanowicz, Kelsey A, Porath, Jonathan D, Hurd, Toby W, Bekker-Jensen, Simon, Schrøder, Jacob Morville, Andersen, Jens S., Hildebrandt, Friedhelm, Airik, Rannar, Schueler, Markus, Airik, Merlin, Cho, Jang, Ulanowicz, Kelsey A, Porath, Jonathan D, Hurd, Toby W, Bekker-Jensen, Simon, Schrøder, Jacob Morville, Andersen, Jens S., and Hildebrandt, Friedhelm

Abstract

Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure.

Published
2016

13. FAT1 mutations cause a glomerulotubular nephropathy

Author

Gee, Heon Yung, Sadowski, Carolin E, Aggarwal, Pardeep K, Porath, Jonathan D, Yakulov, Toma A, Schueler, Markus, Lovric, Svjetlana, Ashraf, Shazia, Braun, Daniela A, Halbritter, Jan, Fang, Humphrey, Airik, Rannar, Vega-Warner, Virginia, Jee Cho, Kyeong, Chan, Timothy A, Morris, Luc G T, Ffrench-Constant, Charles, Allen, Nicholas, McNeill, Helen, Büscher, Rainer, Kyrieleis, Henriette, Wallot, Michael, Gaspert, Ariana, Kistler, Thomas, Milford, David V, Saleem, Moin A, Keng, Wee Teik, Alexander, Stephen I, Valentini, Rudolph P, Licht, Christoph, Teh, Jun C, Bogdanovic, Radovan, Koziell, Ania, Bierzynska, Agnieszka, Soliman, Neveen A, Otto, Edgar A, Lifton, Richard P, Holzman, Lawrence B, Sibinga, Nicholas E S, Walz, Gerd, Tufro, Alda, Hildebrandt, Friedhelm, Gee, Heon Yung, Sadowski, Carolin E, Aggarwal, Pardeep K, Porath, Jonathan D, Yakulov, Toma A, Schueler, Markus, Lovric, Svjetlana, Ashraf, Shazia, Braun, Daniela A, Halbritter, Jan, Fang, Humphrey, Airik, Rannar, Vega-Warner, Virginia, Jee Cho, Kyeong, Chan, Timothy A, Morris, Luc G T, Ffrench-Constant, Charles, Allen, Nicholas, McNeill, Helen, Büscher, Rainer, Kyrieleis, Henriette, Wallot, Michael, Gaspert, Ariana, Kistler, Thomas, Milford, David V, Saleem, Moin A, Keng, Wee Teik, Alexander, Stephen I, Valentini, Rudolph P, Licht, Christoph, Teh, Jun C, Bogdanovic, Radovan, Koziell, Ania, Bierzynska, Agnieszka, Soliman, Neveen A, Otto, Edgar A, Lifton, Richard P, Holzman, Lawrence B, Sibinga, Nicholas E S, Walz, Gerd, Tufro, Alda, and Hildebrandt, Friedhelm

Abstract

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Published
2016

15. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease

Author

Lewis, Wesley R., primary, Malarkey, Erik B., additional, Tritschler, Douglas, additional, Bower, Raqual, additional, Pasek, Raymond C., additional, Porath, Jonathan D., additional, Birket, Susan E., additional, Saunier, Sophie, additional, Antignac, Corinne, additional, Knowles, Michael R., additional, Leigh, Margaret W., additional, Zariwala, Maimoona A., additional, Challa, Anil K., additional, Kesterson, Robert A., additional, Rowe, Steven M., additional, Drummond, Iain A., additional, Parant, John M., additional, Hildebrandt, Friedhelm, additional, Porter, Mary E., additional, Yoder, Bradley K., additional, and Berbari, Nicolas F., additional

Published
2016
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18. FAT1 mutations cause a glomerulotubular nephropathy

Author

Gee, Heon Yung, primary, Sadowski, Carolin E., additional, Aggarwal, Pardeep K., additional, Porath, Jonathan D., additional, Yakulov, Toma A., additional, Schueler, Markus, additional, Lovric, Svjetlana, additional, Ashraf, Shazia, additional, Braun, Daniela A., additional, Halbritter, Jan, additional, Fang, Humphrey, additional, Airik, Rannar, additional, Vega-Warner, Virginia, additional, Cho, Kyeong Jee, additional, Chan, Timothy A., additional, Morris, Luc G. T., additional, ffrench-Constant, Charles, additional, Allen, Nicholas, additional, McNeill, Helen, additional, Büscher, Rainer, additional, Kyrieleis, Henriette, additional, Wallot, Michael, additional, Gaspert, Ariana, additional, Kistler, Thomas, additional, Milford, David V., additional, Saleem, Moin A., additional, Keng, Wee Teik, additional, Alexander, Stephen I., additional, Valentini, Rudolph P., additional, Licht, Christoph, additional, Teh, Jun C., additional, Bogdanovic, Radovan, additional, Koziell, Ania, additional, Bierzynska, Agnieszka, additional, Soliman, Neveen A., additional, Otto, Edgar A., additional, Lifton, Richard P., additional, Holzman, Lawrence B., additional, Sibinga, Nicholas E. S., additional, Walz, Gerd, additional, Tufro, Alda, additional, and Hildebrandt, Friedhelm, additional

Published
2016
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19. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Author

Braun, Daniela A., primary, Schueler, Markus, additional, Halbritter, Jan, additional, Gee, Heon Yung, additional, Porath, Jonathan D., additional, Lawson, Jennifer A., additional, Airik, Rannar, additional, Shril, Shirlee, additional, Allen, Susan J., additional, Stein, Deborah, additional, Al Kindy, Adila, additional, Beck, Bodo B., additional, Cengiz, Nurcan, additional, Moorani, Khemchand N., additional, Ozaltin, Fatih, additional, Hashmi, Seema, additional, Sayer, John A., additional, Bockenhauer, Detlef, additional, Soliman, Neveen A., additional, Otto, Edgar A., additional, Lifton, Richard P., additional, and Hildebrandt, Friedhelm, additional

Published
2016
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20. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling

Author

Schueler, Markus, Braun, Daniela A, Chandrasekar, Gayathri, Gee, Heon Yung, Klasson, Timothy D., Halbritter, Jan, Bieder, Andrea, Porath, Jonathan D, Airik, Rannar, Zhou, Weibin, LoTurco, Joseph J, Che, Alicia, Otto, Edgar A, Böckenhauer, Detlef, Sebire, Neil J, Honzik, Tomas, Harris, Peter C, Koon, Sarah J, Gunay-Aygun, Meral, Saunier, Sophie, Zerres, Klaus, Bruechle, Nadina Ortiz, Drenth, Joost P H, Pelletier, Laurence, Tapia-Páez, Isabel, Lifton, Richard P, Giles, R, Kere, Juha, Hildebrandt, Friedhelm, Schueler, Markus, Braun, Daniela A, Chandrasekar, Gayathri, Gee, Heon Yung, Klasson, Timothy D., Halbritter, Jan, Bieder, Andrea, Porath, Jonathan D, Airik, Rannar, Zhou, Weibin, LoTurco, Joseph J, Che, Alicia, Otto, Edgar A, Böckenhauer, Detlef, Sebire, Neil J, Honzik, Tomas, Harris, Peter C, Koon, Sarah J, Gunay-Aygun, Meral, Saunier, Sophie, Zerres, Klaus, Bruechle, Nadina Ortiz, Drenth, Joost P H, Pelletier, Laurence, Tapia-Páez, Isabel, Lifton, Richard P, Giles, R, Kere, Juha, and Hildebrandt, Friedhelm

Published
2015

21. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling

Author

Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Circulatory Health, Schueler, Markus, Braun, Daniela A, Chandrasekar, Gayathri, Gee, Heon Yung, Klasson, Timothy D., Halbritter, Jan, Bieder, Andrea, Porath, Jonathan D, Airik, Rannar, Zhou, Weibin, LoTurco, Joseph J, Che, Alicia, Otto, Edgar A, Böckenhauer, Detlef, Sebire, Neil J, Honzik, Tomas, Harris, Peter C, Koon, Sarah J, Gunay-Aygun, Meral, Saunier, Sophie, Zerres, Klaus, Bruechle, Nadina Ortiz, Drenth, Joost P H, Pelletier, Laurence, Tapia-Páez, Isabel, Lifton, Richard P, Giles, R, Kere, Juha, Hildebrandt, Friedhelm, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Circulatory Health, Schueler, Markus, Braun, Daniela A, Chandrasekar, Gayathri, Gee, Heon Yung, Klasson, Timothy D., Halbritter, Jan, Bieder, Andrea, Porath, Jonathan D, Airik, Rannar, Zhou, Weibin, LoTurco, Joseph J, Che, Alicia, Otto, Edgar A, Böckenhauer, Detlef, Sebire, Neil J, Honzik, Tomas, Harris, Peter C, Koon, Sarah J, Gunay-Aygun, Meral, Saunier, Sophie, Zerres, Klaus, Bruechle, Nadina Ortiz, Drenth, Joost P H, Pelletier, Laurence, Tapia-Páez, Isabel, Lifton, Richard P, Giles, R, Kere, Juha, and Hildebrandt, Friedhelm

Published
2015

22. Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies

Author

Schueler, Markus, primary, Halbritter, Jan, additional, Phelps, Ian G, additional, Braun, Daniela A, additional, Otto, Edgar A, additional, Porath, Jonathan D, additional, Gee, Heon Yung, additional, Shendure, Jay, additional, O'Roak, Brian J, additional, Lawson, Jennifer A, additional, Nabhan, Marwa M, additional, Soliman, Neveen A, additional, Doherty, Dan, additional, and Hildebrandt, Friedhelm, additional

Published
2015
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23. Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

Author

Halbritter, Jan, Bizet, Albane A, Schmidts, Miriam, Porath, Jonathan D, Braun, Daniela A, Gee, Heon Yung, McInerney-Leo, Aideen M, Krug, Pauline, Filhol, Emilie, Davis, Erica E, Airik, Rannar, Czarnecki, Peter G, Lehman, Anna M, Trnka, Peter, Nitschké, Patrick, Bole-Feysot, Christine, Schueler, Markus, Knebelmann, Bertrand, Burtey, Stéphane, Szabó, Attila J, Tory, Kálmán, Leo, Paul J, Gardiner, Brooke, McKenzie, Fiona A, Zankl, Andreas, Brown, Matthew A, Hartley, Jane L, Maher, Eamonn R, Li, Chunmei, Leroux, Michel R, Scambler, Peter J, Zhan, Shing H, Jones, Steven J, Kayserili, Hülya, Tuysuz, Beyhan, Moorani, Khemchand N, Constantinescu, Alexandru, Krantz, Ian D, Kaplan, Bernard S, Shah, Jagesh V, Hurd, Toby W, Doherty, Dan, Katsanis, Nicholas, Duncan, Emma L, Otto, Edgar A, Beales, Philip L, Mitchison, Hannah M, Saunier, Sophie, and Hildebrandt, Friedhelm

Subjects
Cytoplasmic Dyneins, Male, Cerebellar Ataxia, Ellis-Van Creveld Syndrome, Molecular Sequence Data, Bone and Bones, White People, Craniosynostoses, Asian People, Ectodermal Dysplasia, Report, Genetics, Animals, Humans, Genetics(clinical), Amino Acid Sequence, Alleles, Zebrafish, Intracellular Signaling Peptides and Proteins, Dyneins, Epistasis, Genetic, Fibroblasts, Kidney Diseases, Cystic, Phenotype, Gene Knockdown Techniques, Mutation, Female, sense organs, Retinitis Pigmentosa
Abstract

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

Published
2013

24. Mutations in SPAG1 Cause Primary Ciliary Dyskinesia Associated with Defective Outer and Inner Dynein Arms

Author

Chaki, Moumita, Raidt, Johanna, Jahnke, Charlotte, Dougherty, Gerard W., Hjeij, Rim, Werner, Claudius, Carson, Johnny L., Schueler, Markus, Gee, Heon Yung, Porath, Jonathan D., Wolf, Whitney E., Loges, Niki T., Wallmeier, Julia, Sagel, Scott D., Ostrowski, Lawrence E., Huang, Lu, Baktai, György, Braun, Daniela A., Olivier, Kenneth N., Hazucha, Milan J., Diaz, Katrina A., Knowles, Michael R., Dell, Sharon D., Otto, Edgar A., Hurd, Toby, Halbritter, Jan, Pennekamp, Petra, Olbrich, Heike, Davis, Stephanie D., Ferkol, Thomas W., Leigh, Margaret W., and Yin, Weining

Subjects
otorhinolaryngologic diseases
Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

Published
2013
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25. Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia

Author

Schueler, Markus, Davis, Stephanie D., Liu, Yan, Bower, Raqual, Hellman, Nathan, Tritschler, Douglas, Olivier, Kenneth N., Chaki, Moumita, Zariwala, Maimoona A., Gilberti, Renée M., Otto, Edgar A., Halbritter, Jan, Lovric, Svjetlana, Carson, Johnny L., Atkinson, Jeffry J., Ferkol, Thomas W., Pittman, Jessica E., Pathak, Narendra, Hwang, Daw-Yang, Patel-King, Ramila S., Diaz, Katrina A., O’Toole, Eileen, Austin-Tse, Christina, Hurd, Toby W., Kohl, Stefan, Airik, Rannar, Noone, Peadar G., Gee, Heon Yung, Leigh, Margaret W., Panizzi, Jennifer R., Braun, Daniela A., and Porath, Jonathan D.

Subjects
animal structures, otorhinolaryngologic diseases
Abstract

Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.

Published
2013
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26. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Author

Dell, Sharon D., Al-Mutairi, Dalal A., Hjeij, Rim, Leigh, Margaret W., Kohl, Stefan, Morgan, Lucy C., Olbrich, Heike, Porath, Jonathan D., Kurkowiak, Małgorzata, Gee, Heon Yung, Ferkol, Thomas W., Sagel, Scott D., Spear, Philip C., Dougherty, Gerard W., Hurd, Toby W., Hwang, Daw-Yang, Adan, Mohamed, Olivier, Kenneth N., Halbritter, Jan, Zariwala, Maimoona A., Wolf, Whitney E., Sheridan, Eamonn, Werner, Claudius, Batten, Trevor F.C., Chaki, Moumita, Rosenfeld, Margaret, Burns, Kimberlie A., Loges, Niki T., Esteve-Rudd, Julian, Lovric, Svjetlana, Diaz, Katrina A., and Pittman, Jessica E.

Abstract

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

Published
2013
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27. Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies ImplicateZIC3andFOXF1in Human VATER/VACTERL Association

Author

Hilger, Alina C., primary, Halbritter, Jan, additional, Pennimpede, Tracie, additional, van der Ven, Amelie, additional, Sarma, Georgia, additional, Braun, Daniela A., additional, Porath, Jonathan D., additional, Kohl, Stefan, additional, Hwang, Daw-Yang, additional, Dworschak, Gabriel C., additional, Hermann, Bernhard G., additional, Pavlova, Anna, additional, El-Maarri, Osman, additional, Nöthen, Markus M., additional, Ludwig, Michael, additional, Reutter, Heiko, additional, and Hildebrandt, Friedhelm, additional

Published
2015
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28. TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone

Author

Roberson, Elle C., primary, Dowdle, William E., additional, Ozanturk, Aysegul, additional, Garcia-Gonzalo, Francesc R., additional, Li, Chunmei, additional, Halbritter, Jan, additional, Elkhartoufi, Nadia, additional, Porath, Jonathan D., additional, Cope, Heidi, additional, Ashley-Koch, Allison, additional, Gregory, Simon, additional, Thomas, Sophie, additional, Sayer, John A., additional, Saunier, Sophie, additional, Otto, Edgar A., additional, Katsanis, Nicholas, additional, Davis, Erica E., additional, Attié-Bitach, Tania, additional, Hildebrandt, Friedhelm, additional, Leroux, Michel R., additional, and Reiter, Jeremy F., additional

Published
2015
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29. Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

Author

Halbritter, Jan, primary, Baum, Michelle, additional, Hynes, Ann Marie, additional, Rice, Sarah J., additional, Thwaites, David T., additional, Gucev, Zoran S., additional, Fisher, Brittany, additional, Spaneas, Leslie, additional, Porath, Jonathan D., additional, Braun, Daniela A., additional, Wassner, Ari J., additional, Nelson, Caleb P., additional, Tasic, Velibor, additional, Sayer, John A., additional, and Hildebrandt, Friedhelm, additional

Published
2015
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30. DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling

Author

Schueler, Markus, primary, Braun, Daniela A., additional, Chandrasekar, Gayathri, additional, Gee, Heon Yung, additional, Klasson, Timothy D., additional, Halbritter, Jan, additional, Bieder, Andrea, additional, Porath, Jonathan D., additional, Airik, Rannar, additional, Zhou, Weibin, additional, LoTurco, Joseph J., additional, Che, Alicia, additional, Otto, Edgar A., additional, Böckenhauer, Detlef, additional, Sebire, Neil J., additional, Honzik, Tomas, additional, Harris, Peter C., additional, Koon, Sarah J., additional, Gunay-Aygun, Meral, additional, Saunier, Sophie, additional, Zerres, Klaus, additional, Bruechle, Nadina Ortiz, additional, Drenth, Joost P.H., additional, Pelletier, Laurence, additional, Tapia-Páez, Isabel, additional, Lifton, Richard P., additional, Giles, Rachel H., additional, Kere, Juha, additional, and Hildebrandt, Friedhelm, additional

Published
2015
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31. Mutations of CEP83 Cause Infantile Nephronophthisis and Intellectual Disability

Author

Failler, Marion, primary, Gee, Heon Yung, additional, Krug, Pauline, additional, Joo, Kwangsic, additional, Halbritter, Jan, additional, Belkacem, Lilya, additional, Filhol, Emilie, additional, Porath, Jonathan D., additional, Braun, Daniela A., additional, Schueler, Markus, additional, Frigo, Amandine, additional, Alibeu, Olivier, additional, Masson, Cécile, additional, Brochard, Karine, additional, Hurault de Ligny, Bruno, additional, Novo, Robert, additional, Pietrement, Christine, additional, Kayserili, Hulya, additional, Salomon, Rémi, additional, Gubler, Marie-Claire, additional, Otto, Edgar A., additional, Antignac, Corinne, additional, Kim, Joon, additional, Benmerah, Alexandre, additional, Hildebrandt, Friedhelm, additional, and Saunier, Sophie, additional

Published
2014
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32. Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

Author

Halbritter, Jan, primary, Bizet, Albane A., additional, Schmidts, Miriam, additional, Porath, Jonathan D., additional, Braun, Daniela A., additional, Gee, Heon Yung, additional, McInerney-Leo, Aideen M., additional, Krug, Pauline, additional, Filhol, Emilie, additional, Davis, Erica E., additional, Airik, Rannar, additional, Czarnecki, Peter G., additional, Lehman, Anna M., additional, Trnka, Peter, additional, Nitschké, Patrick, additional, Bole-Feysot, Christine, additional, Schueler, Markus, additional, Knebelmann, Bertrand, additional, Burtey, Stéphane, additional, Szabó, Attila J., additional, Tory, Kálmán, additional, Leo, Paul J., additional, Gardiner, Brooke, additional, McKenzie, Fiona A., additional, Zankl, Andreas, additional, Brown, Matthew A., additional, Hartley, Jane L., additional, Maher, Eamonn R., additional, Li, Chunmei, additional, Leroux, Michel R., additional, Scambler, Peter J., additional, Zhan, Shing H., additional, Jones, Steven J., additional, Kayserili, Hülya, additional, Tuysuz, Beyhan, additional, Moorani, Khemchand N., additional, Constantinescu, Alexandru, additional, Krantz, Ian D., additional, Kaplan, Bernard S., additional, Shah, Jagesh V., additional, Hurd, Toby W., additional, Doherty, Dan, additional, Katsanis, Nicholas, additional, Duncan, Emma L., additional, Otto, Edgar A., additional, Beales, Philip L., additional, Mitchison, Hannah M., additional, Saunier, Sophie, additional, and Hildebrandt, Friedhelm, additional

Published
2013
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33. Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia

Author

Austin-Tse, Christina, primary, Halbritter, Jan, additional, Zariwala, Maimoona A., additional, Gilberti, Renée M., additional, Gee, Heon Yung, additional, Hellman, Nathan, additional, Pathak, Narendra, additional, Liu, Yan, additional, Panizzi, Jennifer R., additional, Patel-King, Ramila S., additional, Tritschler, Douglas, additional, Bower, Raqual, additional, O’Toole, Eileen, additional, Porath, Jonathan D., additional, Hurd, Toby W., additional, Chaki, Moumita, additional, Diaz, Katrina A., additional, Kohl, Stefan, additional, Lovric, Svjetlana, additional, Hwang, Daw-Yang, additional, Braun, Daniela A., additional, Schueler, Markus, additional, Airik, Rannar, additional, Otto, Edgar A., additional, Leigh, Margaret W., additional, Noone, Peadar G., additional, Carson, Johnny L., additional, Davis, Stephanie D., additional, Pittman, Jessica E., additional, Ferkol, Thomas W., additional, Atkinson, Jeffry J., additional, Olivier, Kenneth N., additional, Sagel, Scott D., additional, Dell, Sharon D., additional, Rosenfeld, Margaret, additional, Milla, Carlos E., additional, Loges, Niki T., additional, Omran, Heymut, additional, Porter, Mary E., additional, King, Stephen M., additional, Knowles, Michael R., additional, Drummond, Iain A., additional, and Hildebrandt, Friedhelm, additional

Published
2013
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34. Mutations in SPAG1 Cause Primary Ciliary Dyskinesia Associated with Defective Outer and Inner Dynein Arms

Author

Knowles, Michael R., primary, Ostrowski, Lawrence E., additional, Loges, Niki T., additional, Hurd, Toby, additional, Leigh, Margaret W., additional, Huang, Lu, additional, Wolf, Whitney E., additional, Carson, Johnny L., additional, Hazucha, Milan J., additional, Yin, Weining, additional, Davis, Stephanie D., additional, Dell, Sharon D., additional, Ferkol, Thomas W., additional, Sagel, Scott D., additional, Olivier, Kenneth N., additional, Jahnke, Charlotte, additional, Olbrich, Heike, additional, Werner, Claudius, additional, Raidt, Johanna, additional, Wallmeier, Julia, additional, Pennekamp, Petra, additional, Dougherty, Gerard W., additional, Hjeij, Rim, additional, Gee, Heon Yung, additional, Otto, Edgar A., additional, Halbritter, Jan, additional, Chaki, Moumita, additional, Diaz, Katrina A., additional, Braun, Daniela A., additional, Porath, Jonathan D., additional, Schueler, Markus, additional, Baktai, György, additional, Griese, Matthias, additional, Turner, Emily H., additional, Lewis, Alexandra P., additional, Bamshad, Michael J., additional, Nickerson, Deborah A., additional, Hildebrandt, Friedhelm, additional, Shendure, Jay, additional, Omran, Heymut, additional, and Zariwala, Maimoona A., additional

Published
2013
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35. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Author

Zariwala, Maimoona A., primary, Gee, Heon Yung, additional, Kurkowiak, Małgorzata, additional, Al-Mutairi, Dalal A., additional, Leigh, Margaret W., additional, Hurd, Toby W., additional, Hjeij, Rim, additional, Dell, Sharon D., additional, Chaki, Moumita, additional, Dougherty, Gerard W., additional, Adan, Mohamed, additional, Spear, Philip C., additional, Esteve-Rudd, Julian, additional, Loges, Niki T., additional, Rosenfeld, Margaret, additional, Diaz, Katrina A., additional, Olbrich, Heike, additional, Wolf, Whitney E., additional, Sheridan, Eamonn, additional, Batten, Trevor F.C., additional, Halbritter, Jan, additional, Porath, Jonathan D., additional, Kohl, Stefan, additional, Lovric, Svjetlana, additional, Hwang, Daw-Yang, additional, Pittman, Jessica E., additional, Burns, Kimberlie A., additional, Ferkol, Thomas W., additional, Sagel, Scott D., additional, Olivier, Kenneth N., additional, Morgan, Lucy C., additional, Werner, Claudius, additional, Raidt, Johanna, additional, Pennekamp, Petra, additional, Sun, Zhaoxia, additional, Zhou, Weibin, additional, Airik, Rannar, additional, Natarajan, Sivakumar, additional, Allen, Susan J., additional, Amirav, Israel, additional, Wieczorek, Dagmar, additional, Landwehr, Kerstin, additional, Nielsen, Kim, additional, Schwerk, Nicolaus, additional, Sertic, Jadranka, additional, Köhler, Gabriele, additional, Washburn, Joseph, additional, Levy, Shawn, additional, Fan, Shuling, additional, Koerner-Rettberg, Cordula, additional, Amselem, Serge, additional, Williams, David S., additional, Mitchell, Brian J., additional, Drummond, Iain A., additional, Otto, Edgar A., additional, Omran, Heymut, additional, Knowles, Michael R., additional, and Hildebrandt, Friedhelm, additional

Published
2013
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36. A low-fidelity, high-functionality, inexpensive ultrasound-guided nerve block model.

Author

Micheller, Daniel, Chapman, Matthew J., Cover, Michael, Porath, Jonathan D., Theyyunni, Nik, Kessler, Ross, and Huang, Robert

Subjects
ANESTHESIOLOGY, ANESTHETICS, ANIMALS, BIOLOGICAL models, DISSECTION, FEMORAL nerve, NERVE block, PERIPHERAL nervous system, ULTRASONIC imaging, TREATMENT effectiveness, ANATOMY, EQUIPMENT & supplies
Abstract

The article proposes an ultrasound-guided model for performing nerve blocks within the emergency department.

Published
2017
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37. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Author

Braun, Daniela A., Schueler, Markus, Halbritter, Jan, Gee, Heon Yung, Porath, Jonathan D., Lawson, Jennifer A., Airik, Rannar, Shril, Shirlee, Allen, Susan J., Stein, Deborah, Al Kindy, Adila, Beck, Bodo B., Cengiz, Nurcan, Moorani, Khemchand N., Ozaltin, Fatih, Hashmi, Seema, Sayer, John A., Bockenhauer, Detlef, Soliman, Neveen A., Otto, Edgar A., Lifton, Richard P., and Hildebrandt, Friedhelm

Subjects
chronic kidney disease, pediatric nephrology, genetic kidney disease, whole exome sequencing, mutation analysis, monogenic diseases, increased renal echogenicity, nephronophthisis
Abstract

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering, and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis and allows identification of novel candidate genes.

Published
2015
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38. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease

Author

Lewis, Wesley R., Berbari, Nicolas F., Malarkey, Erik B., Bower, Raqual, Saunier, Sophie, Porath, Jonathan D., Rowe, Steven M., Drummond, Iain A., Porter, Mary E., Antignac, Corinne, Knowles, Michael R., Yoder, Bradley K., Parant, John M., Challa, Anil K., Hildebrandt, Friedhelm, Leigh, Margaret W., Pasek, Raymond C., Zariwala, Maimoona A., Kesterson, Robert A., Birket, Susan E., and Tritschler, Douglas

Subjects
3. Good health
Abstract

Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or ‘primary’ cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh) signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400). While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8). GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC) protein 4 (DRC4) where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR) to generate one of these human missense variants in mice demonstrated that this allele is likely pathogenic.

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