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

Abstract

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 polymor-phism 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.

<i>COL7A1</i> Recessive Mutations in Two Siblings with Distinct Subtypes of Dystrophic Epidermolysis Bullosa: Pruriginosa versus Nails Only

“…Rather, in families with dominant DEB, the intense itching can manifest in 1 or more subjects, but occurrence of at least 1 sibling who does not develop EBP is common. In addition, identical mutations in individuals from different families can result in either EBP or classical DEB forms [4,7,8]. This intra- and interfamilial clinical variability suggests the existence of acquired phenotype-modifying factors.…”

“…Since its first description by McGrath in 1994, more than 50 cases have been reported in the literature, all characterized by intense pruritus and presenting similar clinical manifestations [3,4,6,7,8]. Collectively, about 40 different COL7A1 mutations have been identified, and no consistent genotype-phenotype correlation can be made [2,4,6,7,8]. Rather, in families with dominant DEB, the intense itching can manifest in 1 or more subjects, but occurrence of at least 1 sibling who does not develop EBP is common.…”

“…Patients with EBP show distinctive nodular prurigo-like or hypertrophic lichenoid lesions in all body sites that can be easily reached by scratching such as the arms, legs and upper shoulders, with the shins usually being one of the most affected areas. This phenotype may resemble a chronic inflammatory disease, thereby the primary condition is sometimes misdiagnosed and the correct diagnosis delayed [4]. Another constant finding in EBP patients is the presence of abnormality in the toenail growth with variable grades of dystrophy.…”

Case Report Novel and recurrent COL7A1 mutations in Chinese patients with dystrophic epidermolysis bullosa pruriginosa

“…Identical mutations in the COL7A1 gene can lead to DEB-Pr and the classical form of DEB (Almaani et al, 2009). Although 63 mutations in the COL7A1 gene have been identified in different pedigrees of DEB-Pr, these mutations and their relationship between genotypes and phenotypes remain unclear.…”

“…Theoretically, COL7A1 gene mutations can influence the biosynthesis of collagen VII, resulting in different phenotypes of DEB-Pr (Drera et al, 2006;Dang and Murrell, 2008). Furthermore, although additional immune-mediated factors may be involved in the pathogenesis of DEB-Pr (Jiang et al, 2012), it is unclear whether other genetic, epigenetic, metabolic, or environmental factors contribute to the DEB-Pr phenotype (Almaani et al, 2009). …”