Disruption of a Ciliary B9 Protein Complex Causes Meckel Syndrome |
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| Authors: | William E. Dowdle,Jon F. Robinson,Andreas Kneist,M. Salomé Sirerol-Piquer,Suzanna G.M. Frints,Kevin C. Corbit,Norran A. Zaghloul,Gesina van Lijnschoten,Leon Mulders,Dideke E. Verver,Klaus Zerres,Randall R. Reed,Tania Attié -Bitach,Colin A. Johnson,José Manuel Garcí a-Verdugo,Nicholas Katsanis,Carsten Bergmann,Jeremy F. Reiter |
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| Affiliation: | 1Department of Biochemistry and Biophysics, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA;2Center for Human Disease Modeling, Departments of Cell Biology and Pediatrics, Duke University, Durham, NC 27710, USA;3Department of Human Genetics, RWTH Aachen University, Templergraben 55, 52056 Aachen, Germany;4Department of Cellular Morphology, Unidad Mixta CIPF-UVEG, CIBERNED, Valencia 46012, Spain;5Department of Clinical Genetics, Prenatal Diagnosis and Therapy, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands;6Research School for Oncology and Developmental Biology, GROW, Maastricht University, 6200 MD Maastricht, The Netherlands;7University of Maryland School of Medicine, Baltimore, MD 21201, USA;8Department of Pathology, PAMM, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands;9Department of Gynecology, Maxima Medical Center, 5500 MB Veldhoven, The Netherlands;10Laboratoire de Biologie du Dévelopement, UMR CNRS 7622, Université Pierre et Marie Curie, 9 quai Saint-Bernard, 75005 Paris, France;11Center for Sensory Biology, Johns Hopkins School of Medicine, 430 Rangos Building, 855 N Wolfe St, Baltimore, MD 21205, USA;12Département de Génétique et INSERM U-781, Hôpital Necker-Enfants Malades, Université Paris Descartes, 75006 Paris, France;13Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK;14Department of Comparative Neurology, Cavanilles Institute of Biodiversity and Evolutive Biology (CIBERNED), Poligono La Coma s/n., 46980 Valencia, Spain;15Center for Human Genetics, Bioscientia, Konrad-Adenauer-Str. 17, 55218 Ingelheim, Germany |
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| Abstract: | Nearly every ciliated organism possesses three B9 domain-containing proteins: MKS1, B9D1, and B9D2. Mutations in human MKS1 cause Meckel syndrome (MKS), a severe ciliopathy characterized by occipital encephalocele, liver ductal plate malformations, polydactyly, and kidney cysts. Mouse mutations in either Mks1 or B9d2 compromise ciliogenesis and result in phenotypes similar to those of MKS. Given the importance of these two B9 proteins to ciliogenesis, we examined the role of the third B9 protein, B9d1. Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. These data prompted us to screen MKS patients for mutations in B9D1 and B9D2. We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS, affects an evolutionarily conserved residue, and is absent from controls. Unlike wild-type B9D2 mRNA, the p.Ser101Arg mutation failed to rescue zebrafish phenotypes induced by the suppression of b9d2. With coimmunoprecipitation and mass spectrometric analyses, we found that Mks1, B9d1, and B9d2 interact physically, but that the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, further suggesting that the mutation compromises B9d2 function. Our data indicate that B9d1 is required for normal Hh signaling, ciliogenesis, and ciliary protein localization and that B9d1 and B9d2 are essential components of a B9 protein complex, disruption of which causes MKS. |
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