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

PURPOSE To characterize the disease expression of an autosomal recessive human retinal degeneration associated with a mutation in TULP1 (tubby-like protein 1), a gene with currently unknown function. METHODS Homozygotes and heterozygotes from an extended Dominican kindred with a TULP1 splice-site gene mutation (IVS14+1,G-->A) were studied clinically and with visual function tests. Sequence analysis of TULP1 was also performed in unrelated patients with severe retinal degeneration from a North American clinic population. RESULTS Homozygotes had nystagmus, visual acuity of 20/200 or worse, color vision disturbances, bull's eye maculopathy, and peripheral pigmentary retinopathy. Younger patients had a relatively wide extent of kinetic visual fields; older patients had only peripheral islands. No rod function was measurable by psychophysics in any of the patients; markedly reduced cone function was detectable across the visual field of younger patients and in the remaining peripheral islands of older patients. Rod and cone electroretinograms (ERGs) were not detectable using standard methods; microvolt-level cone ERGs were present in some patients. Heterozygotes had normal visual function. 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-onset, severe retinal degeneration involving macular and peripheral cones and rods. The constellation of phenotypic findings suggests that the TULP1 gene product is critically important for normal photoreceptor function and may play a role in retinal development.