Investigative Report

New Glycine Substitution Mutations in Type VII Collagen Underlying Epidermolysis Bullosa Pruriginosa but the Phenotype is not Explained by a Common Polymorphism in the Matrix Metalloproteinase-1 Gene Promoter

Noor Almaani, Lu Liu, Naomi Harrison, Akio Tanaka, Joey E. Lai-Cheong, Jemima E. Mellerio and John A. McGrath
DOI: 10.2340/00015555-0605


Epidermolysis bullosa (EB) pruriginosa is an unusual variant of dystrophic EB in which intense itching can lead to striking skin changes resembling acquired skin disorders such as nodular prurigo or hypertrophic lichen planus. The molecular pathology involves mutations in the COL7A1 gene, but the nature of the mutations is similar to those seen in other non-pruritic forms of dystrophic EB. The mechanism of the dramatic phenotypic differences is currently unknown. In this study we assessed the incidence of a common functional polymor­phism in the matrix metalloproteinase-1 gene promoter (1G or 2G at nucleotide –1607) in individuals with EB pruriginosa (n = 27) compared with non-itchy dominant dystrophic EB (n = 23), recessive dystrophic EB (n = 25) and normal controls (n = 50). The hypothesis is that the 2G allele, which was previously shown to increase matrix metalloproteinase-1 activity and lead to increased degradation of type VII collagen, could explain the phenotypic heterogeneity encountered in dominant forms of EB, particularly the itchy EB pruriginosa phenotype. The rationale is that increased type VII collagen degradation could trigger an inflammatory response leading to itchy skin characteristic of EB pruriginosa. All 27 individuals with EB pruriginosa were heterozygous for dominant-negative glycine substitution mutations in the COL7A1 gene, six of which have not been reported previously. The frequency of the 2G allele in these subjects (46.3%) was greater than in the controls (42.0%), but less than in non-itchy dominant dystrophic EB (52.2%) or recessive dystrophic EB (62.0%), indicating that variants of a common functional polymorphism in the matrix metalloproteinase-1 gene promoter do not account for the itchy skin phenotype. The pathophysiology of EB pruriginosa remains unexplained.

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