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

Nat Genet. 2010 Feb;42(2):175-80. doi: 10.1038/ng.519. Epub 2010 Jan 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / pathology*
  • Photoreceptor Cells, Vertebrate / ultrastructure
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Retinal Degeneration / genetics
  • Retinal Degeneration / pathology*


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