AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

作者：Louie Carrie M; Caridi Gianluca; Lopes Vanda S; Brancati Francesco; Kispert Andreas; Lancaster Madeline A; Schlossman Andrew M; Otto Edgar A; Leitges Michael; Groene Hermann Josef; Lopez Irma; Gudiseva Harini V; O'Toole John F; Vallespin Elena; Ayyagari Radha; Ayuso Carmen; Cremers Frans P M; den Hollander Anneke I; Koenekoop Robert K; Dallapiccola Bruno; Ghiggeri Gian Marco; Hildebrandt Friedhelm; Valente Enza Maria; Williams David S; Gleeson Joseph G^*

来源：Nature Genetics, 2010, 42(2): 175-U117.

DOI：10.1038/ng.519

Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration(1,2). We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary kidney disease nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in nephronophthisis.

• 出版日期2010-2