A recurrent frameshift mutation in exon 19 of the type VII collagen gene (COL7A1) in Mexican patients with recessive dystrophic epidermolysis bullosa

Abstract

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.

The molecular basis of dystrophic epidermolysis bullosa in Mexico

“…Fifty‐nine of a possible 67 COL7A1 mutations (88%) were identified. Some of the mutations presented here have been reported previously, 11–26 but nine unreported COL7A1 mutations, as well as 11 further patients with a recently described recurrent frameshift mutation, are documented for the first time (see Table 1).…”

“…Assessment of thisgroupof patients has established that the mutation 2470insG is a frequent cause of RDEB in northern Mexico and that haplotype analysis shows it to be a shared mutated ancestral allele. 24 The ®rst patient with this mutation was reported in 1994, 4 a Hispanic Mexican from California who was a compound heterozygote for the COL7A1 mutations 2470insG/3858delG. To this patient, we can now add 21 further individuals with RDEB who harbor this mutation on one or both COL7A1 alleles.…”

“…These 21 patients came from 12 families, only two of which were known to be related; 22 however, all the families originated from northern Mexico and haplotype analysis demonstrated propagation of a common ancestral allele for this mutation. 24 This mutation constitutes the ®rst recurrent Hispanic Mexican COL7A1 mutation and now represents the most frequent mutation demonstrated in patients of any nationality with RDEB. The mutation is expected to lead to a downstream premature termination codon in exon 20 and, by current genotype±phenotype paradigms, to severe mutilating Hallopeau±Siemens RDEB.…”

Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes

“…In Mexican patients with DEB, the mutation 2470insG has been noted recurrently, with .50% of patients harbouring this mutation in a study of 36 people from 21 families; this finding was confirmed in our study by the discovery of the 2470insG mutation in two families of Mexican descent. [39][40][41] Analysis of the splice-junction mutations A relatively large number, almost 17%, of all DEB mutations affected the sequences at the intron-exon borders; these mutations were spread across the COL7A1 gene, from exon 3 to intron 117 (fig 2). To examine the consequences of these mutations, 46 mutations, in which the genetic lesion was in the proximity of the intron-exon border, were analysed by a computational tool developed to predict cryptic splicing.…”

A Novel COL7A1 Gene Mutation in an Iranian Individual Suffering Dystrophic Epidermolysis Bullosa

“…11 The severest forms of RDEB are caused by mutations on both alleles that result in either null alleles or out-of-frame mutations from insertions/deletions, single-base substitutions, and splice junction alterations. 6,10,[12][13][14][15] The severity may be related to the position of the stop codon; however, the presence of some functional protein appears to be the most important factor in ameliorating the disease severity. 16 Here we report a novel homozygous single-base deletion in the COL7A1 gene of a young girl from southwest Iran with a severe form of DEB.…”