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Charles A. Lewis, Iván R. Batlle, Karla G. R. Batlle, Poulabi Banerjee, Artur V. Cideciyan, Jiancheng Huang, Tomás S. Alemán, Yijun Huang, Jurg Ott, T. Conrad Gilliam, James A. Knowles, Samuel G. Jacobson; Tubby-like Protein 1 Homozygous Splice-Site Mutation Causes Early-Onset Severe Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 1999;40(9):2106-2114.
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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
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