AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis
Copyright policy )AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis
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.
- University of California, Los Angeles United States
- Autonomous University of Madrid Spain
- University of California, San Diego United States
- University of Michigan–Flint United States
- University of California System United States
570, Amino Acid Substitution; genetics; Animals; Carrier Proteins; Cell Death; Cell Line; Humans; Italy; Mice; Opsins; metabolism; Photoreceptor Cells; Vertebrate; metabolism/pathology/ultrastructure; Proto-Oncogene Proteins; deficiency/genetics/metabolism; Retinal Degeneration; genetics/pathology, Agricultural Biotechnology, Agricultural biotechnology, Bioinformatics and Computational Biology, 610, Veterinary and Food Sciences, Neurodegenerative, Eye, NCMLS 6: Genetics and epigenetic pathways of disease, Medical and Health Sciences, Cell Line, Mice, IGMD 3: Genomic disorders and inherited multi-system disorders, Proto-Oncogene Proteins, Genetics, Animals, Humans, Photoreceptor Cells, Eye Disease and Disorders of Vision, Adaptor Proteins, Signal Transducing, Agricultural, Cell Death, Opsins, Vertebrate, Retinal Degeneration, Neurosciences, Signal Transducing, Adaptor Proteins, Biological Sciences, Bioinformatics and computational biology, Vesicular Transport, Adaptor Proteins, Vesicular Transport, Cytoskeletal Proteins, Amino Acid Substitution, Italy, Carrier Proteins, Amino Acid Substitution; genetics, Animals, Carrier Proteins; genetics, Cell Death, Cell Line, Humans, Italy, Mice, Opsins; metabolism, Photoreceptor Cells; Vertebrate; metabolism/pathology/ultrastructure, Proto-Oncogene Proteins; deficiency/genetics/metabolism, Retinal Degeneration; genetics/pathology, Developmental Biology, Photoreceptor Cells, Vertebrate
570, Amino Acid Substitution; genetics; Animals; Carrier Proteins; Cell Death; Cell Line; Humans; Italy; Mice; Opsins; metabolism; Photoreceptor Cells; Vertebrate; metabolism/pathology/ultrastructure; Proto-Oncogene Proteins; deficiency/genetics/metabolism; Retinal Degeneration; genetics/pathology, Agricultural Biotechnology, Agricultural biotechnology, Bioinformatics and Computational Biology, 610, Veterinary and Food Sciences, Neurodegenerative, Eye, NCMLS 6: Genetics and epigenetic pathways of disease, Medical and Health Sciences, Cell Line, Mice, IGMD 3: Genomic disorders and inherited multi-system disorders, Proto-Oncogene Proteins, Genetics, Animals, Humans, Photoreceptor Cells, Eye Disease and Disorders of Vision, Adaptor Proteins, Signal Transducing, Agricultural, Cell Death, Opsins, Vertebrate, Retinal Degeneration, Neurosciences, Signal Transducing, Adaptor Proteins, Biological Sciences, Bioinformatics and computational biology, Vesicular Transport, Adaptor Proteins, Vesicular Transport, Cytoskeletal Proteins, Amino Acid Substitution, Italy, Carrier Proteins, Amino Acid Substitution; genetics, Animals, Carrier Proteins; genetics, Cell Death, Cell Line, Humans, Italy, Mice, Opsins; metabolism, Photoreceptor Cells; Vertebrate; metabolism/pathology/ultrastructure, Proto-Oncogene Proteins; deficiency/genetics/metabolism, Retinal Degeneration; genetics/pathology, Developmental Biology, Photoreceptor Cells, Vertebrate
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