Tubby-like protein 1 homozygous splice-site mutation causes early-onset severe retinal degeneration

PURPOSE. To characterize the disease expression of an autosomal recessive h uman retinal degeneration associated with a mutation in TULP1 (tubby-like p rotein 1), a gene with currently unknown function. METHODS. Homozygotes and heterozygotes from an extended Dominican kindred w ith a TULP1 splice-site gene mutation (IVS14 + 1, G-->A) were studied clini cally and with visual function tests. Sequence analysis of TULP1 was also p erformed in unrelated patients with severe retinal degeneration from a Nort h American clinic population. RESULTS. Homozygotes had nystagmus, visual acuity of 20/200 or morse, color vision disturbances, bull's eye maculopathy, and peripheral pigmentary ret inopathy. Younger patients had a relatively wide extent of kinetic visual f ields: older patients had only peripheral islands. No rod function was meas urable by psychophysics in any of the patients; markedly reduced cone funct ion was detectable across the visual field of younger patients and in the r emaining peripheral islands of older patients. Rod and cone electroretinogr ams (ERGs) were not detectable using standard methods; microvolt-level cone ERGs were present in some patients. Heterozygotes had normal visual functi on. No putative pathogenic sequence changes in TULP1 were observed in North American patients with comparably severe retinal phenotypes, mainly in the diagnostic category of Leber congenital amaurosis. CONCLUSIONS. This TULP1 splice-site mutation in homozygotes causes early-on set, severe retinal degeneration involving macular and peripheral cones and rods. The constellation of phenotypic findings suggests that the TULP1 gen e product is critically important for normal photoreceptor function and may play a role in retinal development.