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.
Louie
Carrie M
CM
Howard Hughes Medical Institute, Department of Pediatrics, University of California, San Diego, La Jolla, USA.
Caridi
Gianluca
G
Lopes
Vanda S
VS
Brancati
Francesco
F
Kispert
Andreas
A
Lancaster
Madeline A
MA
Schlossman
Andrew M
AM
Otto
Edgar A
EA
Leitges
Michael
M
Gröne
Hermann-Josef
HJ
Lopez
Irma
I
Gudiseva
Harini V
HV
O'Toole
John F
JF
Vallespin
Elena
E
Ayyagari
Radha
R
Ayuso
Carmen
C
Cremers
Frans P M
FP
den Hollander
Anneke I
AI
Koenekoop
Robert K
RK
Dallapiccola
Bruno
B
Ghiggeri
Gian Marco
GM
Hildebrandt
Friedhelm
F
Valente
Enza Maria
EM
Williams
David S
DS
Gleeson
Joseph G
JG
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*
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