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J. Zenteno, R. Garnica–Hayashi, M.A. Quiróz, F. Graue–Wiechers; A Novel REP–1 R270X Mutation in a Mexican Family With Choroideremia . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5801.
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© ARVO (1962-2015); The Authors (2016-present)
Choroideremia (CHM; MIM #303100) is an X–linked recessive progressive chorioretinal degeneration first described in 1871 by Mauthner. Night blindness and progressive loss of peripheral vision become evident by the second and third decade of life in most patients with progression to tunnel vision or complete blindness by middle age. Histologically, there is degeneration of the retinal pigment epithelium and its two adjacent cell layers, the choroid which contains the blood vessels, and the retinal photoreceptor cells. The disease results from mutations in the CHM gene, located in Xq21. The product of this gene, Rab escort protein (REP)–1, is involved in the posttranslational lipid modification and subsequent membrane targeting of Rab proteins, small GTPases that play a key role in intracellular trafficking. All mutations in the choroideremia gene result in the truncation or absence of the normal protein product REP–1. We describe the clinical and molecular analysis of a Mexican family with CHM. Fifteen members of a CHM family, including 3 affected males, 2 obligate carrier females, 6 asymptomatic females and 4 asymptomatic males,
The ophthalmologic examination included best–corrected visual acuity, color vision tests, slit–lamp examination, fundus examination, Goldmann visual fields, electroretinography, and fluorescein angiography. To detect mutations of the CHM gene, genomic DNA was extracted from peripheral leukocytes, all 15 exons of the CHM gene amplified by PCR and the products of polymerase chain reaction directly sequenced in both directions in all affected males. In the other relatives, only the exon containing the mutation was examined.
Fundus examination in affected males revealed mottling of the RPE without macular involvement typical of CHM. There was evidence of differences in fundus findings between some carrier females. CHM gene analysis revealed a novel C to T mutation at nucleotide 838 in exon 6, which predicts a R270X nonsense mutation. The mutation was confirmed in all 3 affected males, in 2 obligate female carriers and in 4 asymptomatic females.
This is the first description of molecular analysis in Mexican patients with CHM; our results expand the mutational espectrum of the CHM gene in choroideremia; there were instances of phenotypic variability in fundus appearance between some carrier females indicating that other factors can modulate the expression of the mutation in the heterozygous state.
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