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

Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE

Original Publication: New York, NY : Nature Pub. Co., c1992-

Photoreceptor Cells, Vertebrate/*pathology ; Proto-Oncogene Proteins/*metabolism ; Retinal Degeneration/*pathology; Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Amino Acid Substitution/genetics ; Animals ; Carrier Proteins/genetics ; Cell Death ; Cell Line ; Cytoskeletal Proteins ; Humans ; Italy ; Mice ; Opsins/metabolism ; Photoreceptor Cells, Vertebrate/metabolism ; Photoreceptor Cells, Vertebrate/ultrastructure ; Proto-Oncogene Proteins/deficiency ; Proto-Oncogene Proteins/genetics ; Retinal Degeneration/genetics

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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R01 EY013408-05A2 United States EY NEI NIH HHS; F31NS059281 United States NS NINDS NIH HHS; P30NS047101 United States NS NINDS NIH HHS; R01EY007042 United States EY NEI NIH HHS; R01DK068306 United States DK NIDDK NIH HHS; R01 EY007042 United States EY NEI NIH HHS; R01 NS048453 United States NS NINDS NIH HHS; R01 DK068306 United States DK NIDDK NIH HHS; GGP08145 Italy TI_ Telethon; T32 GM008666 United States GM NIGMS NIH HHS; F31 NS059281 United States NS NINDS NIH HHS; R01 EY013408 United States EY NEI NIH HHS; R01NS048453 United States NS NINDS NIH HHS; P30 NS047101 United States NS NINDS NIH HHS

0 (Adaptor Proteins, Signal Transducing)
0 (Adaptor Proteins, Vesicular Transport)
0 (Ahi1 protein, mouse)
0 (Carrier Proteins)
0 (Cytoskeletal Proteins)
0 (Nphp1 protein, mouse)
0 (Opsins)
0 (Proto-Oncogene Proteins)

Date Created: 20100119 Date Completed: 20100217 Latest Revision: 20211020

20240104

PMC2884967

10.1038/ng.519

20081859