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1 From the Riverview Medical Center, Carrabelle, Florida; 2 Oftalmologia Especializada, Santo Domingo, Dominican Republic; the 3 Departments of Genetics and Development and Psychiatry, Columbia Genome Center, College of Physicians and Surgeons at Columbia University and New York Psychiatric Institute, New York; the 4 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia; and 5 Rockefeller University, Laboratory of Statistical Genetics, New York, New York.
Abstract
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.
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