Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
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The authors thank the families who contributed to this study. We thank Vivette D. D’Agati and Michael B. Stokes (Columbia University) for a kidney biopsy report and images, as well as Gérard Pivert (Pathology Department, Necker Hospital) for kidney biopsy. We are grateful to James Sillibourne for his kind gift of the CEP89 antibody. We also thank Patrick Nitschké and the bioinformatic Plateform (Université Paris Descartes, Institut Imagine) as well as Christine Bole-Feysot, Solenn Pruvost, and Mohammed Zarhrate for their support in exome sequencing and Ludovic Lecompte and Lucie Sengmanivong from the Nikon Imaging Centre at Institut Curie-CNRS (Paris, France) for the help with the n-SIM. This research was supported by a grant from the NIH to F.H. (DK068306). H.Y.G. is a Research Fellow of the American Society of Nephrology (ASN). F.H. is an Investigator of the Howard Hughes Medical Institute and Warren E. Grupe Professor of Pediatrics at the Harvard Medical School. This work was supported by grants from the “Agence Nationale de la Recherche” (ANR) to S.S. (20100BLAN112202) and investments for the future program-ANR-10-IAHY-01 to S.S., the “Fondation pour la Recherche Médicale” (FRM) to S.S. (DEQ20071210558) and to P.K. (DEA20120624188); M.F. is supported by a fellowship from the “Région ile de France, CORDDIM” (RPH12173KKA).
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