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H. J. Perez-Cano, J. C. Zenteno; Molecular Analysis of the CHM Gene and of the X-Chromosome Inactivation Pattern in Two Mexican Families With Choroideremia. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3107.
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Choroideremia is a retinal degeneration resulting from atrophy of both choroidal and retinal pigment ephitelium layers. Choroideremia is transmitted as an X-linked recessive trait. The gene responsible of this disease, CHM,is localized at Xq21 and codes for the Rab Escort Protein-1 (REP-1). All CHM gene mutations reported to date result in premature truncation or absence of the normal protein product. Women with CHM mutations are disease carriers that normally does not exhibit phenotypic expression. However, several cases of affected females have been reported, presumably due to non random or skewed X-chromosome inactivation towards the X chromosome with the normal CHM allele. The aim of this work was to identify mutations in the CHM gene in two Mexican families with choroideremia and to determinate the X- inactivation pattern in female carriers.
Two Mexican families with choroideremia were analyzed. Family 1 was composed of 17 subjects including 3 affected males, 6 healthy males, 1 affected female, and 7 unaffected females. Family 2 was composed of 7 subjects including 2 affected males and 5 unaffected females. DNA was extracted from peripheral blood leukocytes and the 15 exons of the CHM gene were amplified by PCR. Direct nucleotide sequencing was performed using fluorescent terminators. The X-inactivation pattern was determined using the androgen receptor CAG repeat assay.
In family 1 a nosense mutation was identified: arginine at position 270 (CGA) changed to a stop codon (TGA), R270X. In family 2, a novel nonsense mutation was identified at codón 468 (exon 11) predicting the change of serine (TCA) to a stop codón (TGA), S468X. Of the 13 females included in the study, 10 were demonstrated to be carriers. Of these, nine females (including the affected one from family 1) had a random X inactivation pattern (family 1 average: 54% vs 46%; family 2 average: 51% vs 49%). One female from family 2 demonstrated a skewed X-inactivation pattern, 68% vs 32%. This 26-year-old female exhibited retinal lesions reminiscent of the disease, however her X-chromosome preferentially inactivated was the one carrying the mutated allele.
A novel S468X CHM gene mutation was identified in a Mexican case of choroideremia, expanding the mutational spectrum of the disease. Our results suggest that X-inactivation plays no a role in determining the retinal phenotype in heterozygous females that manifest the disease. However, it is possible that in retinal cells the X-chromosome inactivation pattern be different from peripheral leukocytes.
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