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

CM Louie, G Caridi, VS Lopes, F Brancati, A Kispert… - Nature …, 2010 - nature.com
CM Louie, G Caridi, VS Lopes, F Brancati, A Kispert, MA Lancaster, AM Schlossman…
Nature genetics, 2010nature.com
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 …
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.
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