학술논문
AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis
Document Type
article
Author
Louie, Carrie M; Caridi, Gianluca; Lopes, Vanda S; Brancati, Francesco; Kispert, Andreas; Lancaster, Madeline A; Schlossman, Andrew M; Otto, Edgar A; Leitges, Michael; Gröne, Hermann-Josef; Lopez, Irma; Gudiseva, Harini V; O'Toole, John F; Vallespin, Elena; Ayyagari, Radha; Ayuso, Carmen; Cremers, Frans PM; den Hollander, Anneke I; Koenekoop, Robert K; Dallapiccola, Bruno; Ghiggeri, Gian Marco; Hildebrandt, Friedhelm; Valente, Enza Maria; Williams, David S; Gleeson, Joseph G
Source
Nature Genetics. 42(2)
Subject
Language
Abstract
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. 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.