A founder synonymous COL7A1 mutation in three Danish families with dominant dystrophic epidermolysis bullosa pruriginosa identifies exonic regulatory sequences required for exon 87 splicing

• Published in: British journal of dermatology (1951) Vol. 165; no. 3; pp. 678 - 682
• Main Authors: Covaciu, C., Grosso, F., Pisaneschi, E., Zambruno, G., Gregersen, P.A., Sommerlund, M., Hertz, J.M., Castiglia, D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Wiley-Blackwell
• Subjects: Adolescent; Adult; Biological and medical sciences; Bullous diseases of the skin; Collagen; Collagen (type VII); Collagen Type VII - genetics; Computer applications; Dermatology; Dystrophic epidermolysis bullosa; Enhancers; Epidermolysis Bullosa Dystrophica - genetics; Exons; Exons - genetics; Female; Founder Effect; Genetic counselling; Haplotypes; Heterozygote; Humans; Leg; Male; Medical sciences; Middle Aged; Mutation; Mutation - genetics; Pedigree; pruritus; Regulatory sequences; RNA Splicing - genetics; Splicing; Translation; Denmark; Europe; Bullous dermatosis; Skin disease; Exon; Splicing; Dermatology; Family study; Danish; Mutation; Genetic disease; Dystrophic epidermolysis bullosa
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1111/j.1365-2133.2011.10414.x

Dystrophic epidermolysis bullosa pruriginosa (DEB‐Pr) (OMIM 604129) represents a distinct variant within the DEB clinical spectrum.1 It is characterized by intense pruritus and distinctive nodular prurigo‐like and/or hypertrophic lichenoid lesions mainly localized on the arms, legs and upper shoulders.2 DEB‐Pr is caused by either dominant (DDEB‐Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII).3–5 The full spectrum of COL7A1 mutations in DEB‐Pr remains elusive and the genotype–phenotype correlation is largely incomplete. Here, we report and functionally characterize a previously unrecognized translationally silent exonic COL7A1 mutation that results in skipping of exon 87 and is associated with DDEB‐Pr phenotypes in several members of three apparently unrelated Danish families. A haplotype segregation study suggested a common ancestor in these kindred. Functional splicing analysis of the mutant exon by a COL7A1 minigene construct and computational prediction for splicing regulatory cis‐sequences prove that the mutation alters the activity of an exonic splicing enhancer (ESE) critical for exon inclusion.6,7 These findings substantiate for the first time the involvement of an ESE mutation in the pathogenesis of DEB and have implications for genetic counselling of Danish families with DDEB.