title: Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis.
abstract: Mutations in the human NPHP5 gene cause retinal and renal disease, but the precise mechanism by which NPHP5 functions is not understood. We report that NPHP5 is a centriolar protein whose depletion inhibits an early step of ciliogenesis, a phenotype reminiscent of Cep290 loss and contrary to IFT88 loss. Functional dissection of NPHP5 interactions with Cep290 and CaM reveals a requirement of the former for ciliogenesis, while the latter prevents NPHP5 self-aggregation. Disease-causing mutations lead to truncated products unable to bind Cep290 and localize to centrosomes, thereby compromising cilia formation. In contrast, a modifier mutation cripples CaM binding but has no overt effect on ciliogenesis. Drugs that antagonize negative regulators of the ciliogenic pathway can rescue ciliogenesis in cells depleted of NPHP5, with response profiles similar to those of Cep290- but not IFT88-depleted cells. Our results uncover the underlying molecular basis of disease and provide novel insights into mitigating NPHP5 deficiency.
authors: Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7.
authors: Marine
authors: M
authors: Barbelanne
authors: Jenny
authors: J
authors: Song
authors: Mustafa
authors: M
authors: Ahmadzai
authors: William Y
authors: WY
authors: Tsang
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002502:Centrioles / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D000072661:Ciliopathies; D003598:Cytoskeletal Proteins; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015418:Optic Atrophies, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D000951:Antigens, Neoplasm; D002148:Calmodulin-Binding Proteins; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; C498171:IQCB1 protein, human; D009363:Neoplasm Proteins