title: AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, University of California, San Diego, La Jolla, USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Louie
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Vanda S
authors.initials: VS
authors.lastname: Lopes
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Madeline A
authors.initials: MA
authors.lastname: Lancaster
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schlossman
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Harini V
authors.initials: HV
authors.lastname: Gudiseva
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Elena
authors.initials: E
authors.lastname: Vallespin
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death; D002460:Cell Line; D003598:Cytoskeletal Proteins; D006801:Humans; D007558:Italy; D051379:Mice; D055355:Opsins / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C534985:Nphp1 protein, mouse; D055355:Opsins; D011518:Proto-Oncogene Proteins