RESUMO
A 32-basepair deletion polymorphism in the CCR5 chemokine receptor gene (DeltaCCR5) has recently been identified and shown to have functional significance in determining susceptibility to infection by human immunodeficiency virus type 1 (HIV-1) and a possible influence on disease progression in HIV-1-positive individuals. Interest has also focused on the geographical distribution of the DeltaCCR5 allele, particularly in considering epidemiological aspects of HIV disease and its impact on health economics. In this report we have assessed the frequency of the DeltaCCR5 allele in a Hispanic Mexican population and found a gene frequency of 4.4% in 103 individuals. The DeltaCCR5 allele is not present in indigenous Mexican populations but is present in about 8% of the population in Spain. Gene flow from the European gene pool consistent with Mexico's colonial past would account for the findings in this study.
Assuntos
Americanos Mexicanos/genética , Receptores CCR5/genética , Deleção de Sequência , Alelos , Frequência do Gene , Predisposição Genética para Doença , Infecções por HIV/genética , HIV-1 , HumanosRESUMO
Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disorder caused by mutations in the type VII collagen gene (COL7A1). In this study, we determined the molecular basis of autosomal recessive DEB in a 19-year-old Hispanic Mexican woman by PCR amplification of genomic DNA, heteroduplex analysis, and automated sequencing of heteroduplex bandshifts. This approach revealed a homozygous frameshift mutation, 2470insG, in exon 19 of COL7A1 and resulted in attenuated basement membrane zone expression of type VII collagen, a reduced number of anchoring fibrils at the dermal-epidermal junction, and a sub-lamina densa level of blister formation. Clinically, the patient had widespread trauma-induced skin fragility and complete loss of the nails, but had less pseudosyndactyly of the fingers and toes and milder mucosal involvement compared to most patients with the generalized form of this genodermatosis. We also screened 7 other Hispanic-Mexican patients with recessive DEB, none of whom were known to be related to this individual, for the mutation 2470insG using heteroduplex analysis and direct sequencing and detected this mutation on 7/14 alleles. Haplotype analysis using intragenic COL7A1 and flanking polymorphisms and microsatellite markers revealed that all the mutant alleles had arisen on similar allelic backgrounds, consistent with propagation of a common Hispanic Mexican ancestral haplotype. In view of the high allelic frequency of the mutation 2470insG in the patients studied, we recommend initial screening for this mutation when attempting to identify the molecular pathology of recessive DEB in Hispanic Mexican patients.
Assuntos
Colágeno/genética , Epidermólise Bolhosa Distrófica/genética , Éxons/genética , Adulto , Colágeno/análise , DNA/análise , DNA/genética , Epidermólise Bolhosa Distrófica/metabolismo , Saúde da Família , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Análise Heteroduplex , Humanos , Imuno-Histoquímica , México , Linhagem , Pele/química , Pele/patologia , Pele/ultraestruturaRESUMO
Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). In this study, we assessed the molecular basis of recessive DEB in five affected individuals from two Mexican families. Both fathers of the affected children were first cousins. Genomic DNA was extracted from peripheral blood samples and assessed for COL7A1 mutations by polymerase chain reaction (PCR) amplification, heteroduplex analysis and direct automated sequencing of PCR products displaying heteroduplex bandshifts. In one family, we identified a homozygous 1 bp insertion of a G nucleotide in exon 19 of COL7A1, designated 2470insG, in three affected sisters. This mutation causes a frameshift and a premature termination codon on both alleles 178 bp downstream from the insertion; both parents were shown to be heterozygous carriers of this mutation. In the second family, the father of the other two affected children was also found to be a heterozygous carrier of this frameshift mutation. In addition, his unrelated partner was shown to be a heterozygous carrier of a different COL7A1 frameshift mutation, an insertion of a T nucleotide in exon 32, designated 3948insT. This mutation also results in a premature termination codon, 126 bp downstream from the insertion. Both affected children were compound heterozygotes for the 2470insG/3948insT mutations in COL7A1. Overall, these molecular findings offer a genetic explanation for the skin fragility in these related Mexican patients with recessive DEB. Immediate benefits from elucidation of the mutations include assessment of carrier status in other members of the family and the feasibility of DNA-based prenatal testing in subsequent pregnancies.
Assuntos
Colágeno/genética , Epidermólise Bolhosa Distrófica/genética , Mutação da Fase de Leitura , Adolescente , Adulto , Criança , Epidermólise Bolhosa Distrófica/patologia , Feminino , Genes Recessivos , Humanos , Masculino , México , Ácidos Nucleicos Heteroduplexes/genética , Linhagem , Reação em Cadeia da PolimeraseRESUMO
Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). Nearly all cases of dominant DEB are caused by glycine substitution mutations occurring within the triple helical region of type VII collagen, and most of the mutations are unique to individual families. In this study, we identified a patient of Hispanic-Mexican origin with a mild form of DEB, which resulted from a de novo dominant glycine substitution, G2043R, in exon 73 of COL7A1. We also investigated a Scottish family with a three-generation pedigree of dominant DEB, in whom the same glycine to arginine substitution mutation was demonstrated. This particular mutation has also been detected previously in three other families with dominant DEB: one Italian, one Hungarian and one Norwegian. Given the widespread geographical distribution of this mutation and the demonstration of its occurrence as a de novo event, G2043R therefore represents the first example of a mutational hotspot in dominant DEB. Interestingly, although both the Mexican and Scottish families we studied had some clinical features in keeping with the Pasini form of the disorder, there was considerable interfamilial variability as well as intrafamilial diversity in the affected individuals.