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

• Published in: Nature genetics Vol. 42; no. 2; pp. 175 - 180
• Main Authors: den Hollander, Anneke I, Dallapiccola, Bruno, Ayuso, Carmen, Caridi, Gianluca, Brancati, Francesco, Kispert, Andreas, Gudiseva, Harini V, Louie, Carrie M, Koenekoop, Robert K, Ayyagari, Radha, Leitges, Michael, Lopez, Irma, Vallespin, Elena, Otto, Edgar A, Williams, David S, Lopes, Vanda S, Valente, Enza Maria, Gleeson, Joseph G, Lancaster, Madeline A, Cremers, Frans P M, Hildebrandt, Friedhelm, O'Toole, John F, Gröne, Hermann-Josef, Ghiggeri, Gian Marco, Schlossman, Andrew M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2010; Nature Publishing Group
• Subjects: 631/208/366; 631/208/727/2000; Agriculture; Amino Acid Substitution - genetics; Animal Genetics and Genomics; Animals; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carrier Proteins - genetics; Cell Death; Cell Line; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; Italy; Kidney diseases; letter; Medical sciences; Mice; Mortality; Ophthalmology; Opsins - metabolism; Photoreception; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptor Cells, Vertebrate - pathology; Photoreceptor Cells, Vertebrate - ultrastructure; Photoreceptors; Physiological aspects; Proteins; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinopathies; Risk factors; Signal transduction; Italy; United States; Eye; Macular degeneration; Visual system; Eye disease; Retinopathy; Photoreceptor; Development; Retina
• ISSN: 1061-4036; 1546-1718
• 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. 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.