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 degeneration1,2. 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.
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Acknowledgements
We thank K. Siever and K. Teofilo for assistance with histology; G. Silva, L. Cheng and M. Davidson for assistance with ERG testing; A. Avila for assistance with clinical data and selecting controls; J. Lem, G. Lemke, T. Burstyn-Cohen and A. Wynshaw-Boris for sharing mice and for feedback and suggestions; K. Zhang, L. Goldstein and B. Zheng for feedback and suggestions; T. Li and E. Pierce for sharing antibodies; C.-H. Sung for sharing rhodopsin plasmid; J. Kim and V. Cantagrel for technical advice; and J. Meerloo with the University of California at San Diego (UCSD) Neurosciences Microscopy Shared Facility (NINDS P30NS047101) for microscopy services and support. This work was supported by the US National Institutes of Health R01NS048453 (J.G.G.), R01DK068306 (F.H.), P30NS047101 (J.G.G.), F31NS059281 (C.M.L.), R01EY007042 (D.S.W.), UCSD Genetics Training Program institutional training grant T32 GM008666 from the National Institute for General Medical Sciences (C.M.L. and M.A.L), GP08145 grant from Telethon-Italy (E.M.V.) and the Burroughs Wellcome Fund (J.G.G.). D.S.W. is a Jules and Doris Stein RPB Professor. J.G.G. and F.H. are investigators of the Howard Hughes Medical Institute.
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C.M.L and J.G.G. designed the study and experiments with substantial contributions from D.S.W. C.M.L., A.K., F.H. and M.L. developed mutant mice and C.M.L., E.A.O., F.H., H.-J.G. and J.F.O. performed initial characterization. C.M.L. performed mouse experiments. V.S.L. performed electron microscopy. G.C., E.M.V., G.M.G. and B.D. ascertained and supervised genotyping of affected persons and contributed to analysis. A.I.d.H., R.K.K. and F.P.M.C. contributed LCA samples and screened a portion of individuals with LCA. C.A., R.A., H.V.G. and E.V. contributed samples for the LCA study. F.B., I.L., A.M.S. and C.M.L. performed genetic screening and genotyping. M.A.L. performed biochemical assays. C.M.L. and J.G.G. wrote the manuscript with contributions from E.M.V., G.C., D.S.W., V.S.L., F.H., F.B. and A.K.
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Louie, C., Caridi, G., Lopes, V. et al. AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet 42, 175–180 (2010). https://doi.org/10.1038/ng.519
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DOI: https://doi.org/10.1038/ng.519