期刊
HUMAN MUTATION
卷 35, 期 1, 页码 137-146出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.22470
关键词
Joubert syndrome; primary cilia; PDE6D; INPP5E; prenylation
资金
- Agence Nationale de la Recherche [ANR 1122 01 FOETOCILPATH]
- IMAGINE Institute
- Fondation pour la Recherche Medicale [FRM DEQ20071210558]
- National Institutes of Health [DK053093, DK070263, NS048453]
- European Research Council (ERC) [260888]
- Italian Ministry of Health
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P01HD070494] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [P30EY014800, R01EY008123] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK070263, R01DK053093] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS048453, R01NS052455] Funding Source: NIH RePORTER
Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.
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