Allelic Heterogeneity of Dominant and Recessive COL7A1 Mutations Underlying Epidermolysis Bullosa Pruriginosa

Department of Cell and Molecular Pathology, St John's Institute of Dermatology (The Guy's, King's College and St Thomas' Hospitals' Medical School), London, UK.
Journal of Investigative Dermatology (Impact Factor: 7.22). 05/1999; 112(6):984-987. DOI: 10.1046/j.1523-1747.1999.00614.x


The inherited mechanobullous disease, dystrophic epidermolysis bullosa, is caused by type VII collagen gene (COL7A1) mutations. We studied six unrelated patients with a distinct clinical subtype of this disease, epidermolysis bullosa pruriginosa, characterized by pruritus, excoriated prurigo nodules, and skin fragility. Mutation analysis using polymerase chain reaction amplification of genomic DNA, heteroduplex analysis and direct nucleotide sequencing demonstrated pathogenetic COL7A1 mutations in each case. Four patients had a glycine substitution mutation on one COL7A1 allele (G1791E, G2242R, G2369S, and G2713R), a fifth was a compound heterozygote for a splice site mutation (5532 + 1G-to-A) and a single base pair deletion (7786delG), and a sixth patient was heterozygous for an out-of-frame deletion mutation (6863del16). This study shows that the molecular pathology in patients with the distinctive clinical features of epidermolysis bullosa pruriginosa is heterogeneous and suggests that other factors, in addition to the inherent COL7A1 mutation(s), may be responsible for an epidermolysis bullosa pruriginosa phenotype.Keywords: basement membrane zone, genetic blistering skin disease, pruritus

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Available from: Julio Salas, Mar 18, 2014
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    • "The link between EBP and atopy is controversial. A history of atopy, in the probands themselves or in their relatives, might predispose some individuals to develop EBP instead of DEB, but genotypes associated with atopy such as filaggrin mutations and IL-31 polymorphisms are not consistently different between people with EBP and those with DEB (7,9,10). Some people with EBP have high IgE levels, but most have normal levels (3). "
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    ABSTRACT:   Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by intense pruritus, nodular or lichenoid lesions, and violaceous linear scarring, most prominently on the extensor extremities. Remarkably, identical mutations in COL7A1, which encodes an anchoring fibril protein present at the dermal-epidermal junction, can cause both DEB and EBP with either autosomal dominant or recessive inheritance. We present one family with both dystrophic and pruriginosa phenotypes of epidermolysis bullosa. The proband is a 19-year-old Caucasian woman who initially presented in childhood with lichenoid papules affecting her extensor limbs and intense pruritus consistent with EBP. Her maternal grandmother saw a dermatologist for similar skin lesions that developed without any known triggers at age 47 and mostly resolved spontaneously after approximately 10 years. The proband's younger brother developed a small crop of pruritic papules on his elbows, dorsal hands, knees, and ankles at age 13. Her second cousin once removed, however, reported a mild blistering disease without pruritus consistent with DEB. Genetic sequencing of the kindred revealed a single dominant novel intron 47 splice site donor G>A mutation, c.4668 + 1 G>A, which we predict leads to exon skipping. Incomplete penetrance is confirmed in her clinically unaffected mother, who carries the same dominant mutation. The wide diversity of clinical phenotypes with one underlying genotype demonstrates that COL7A1 mutations are incompletely penetrant and strongly suggests that other genetic and environmental factors influence clinical presentation.
    Pediatric Dermatology 04/2012; 29(6). DOI:10.1111/j.1525-1470.2012.01757.x · 1.02 Impact Factor
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    • "This study also included three patients with rare variants of DEB (Fine et al, 2000), the pretibial and inversa DEB forms, currently classi¢ed as dominantly and recessively inherited, respectively . The two Pt-RDEB patients, one novel and the other one previously described (Betts et al, 1999), represent the only two clear cases in which an autosomal recessive inheritance pattern has been established, although Mellerio et al (1999) reported a compound heterozygote (7786delG/5532 þ 1G-A) who had DEB pruriginosa but clinical features most apparent on the shins. Together with a few autosomal dominant cases previously reported (Lee et al, 1993; Christiano et al, 1995), our data support the notion that Pt-DEB can be either dominantly or recessively inherited. "
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    ABSTRACT: Dystrophic epidermolysis bullosa (DEB) is a rare skin disorder that is clinically heterogeneous and is transmitted either in dominant (DDEB) or recessive (RDEB) mode. Nevertheless, all variants of DEB are caused by mutations in type VII collagen gene (COL7A1). We report an analysis of COL7A1 mutations in 51 Italian DEB patients, 27 affected with Hallopeau-Siemens RDEB, 19 with non Hallopeau-Siemens RDEB, two with DDEB, two with pretibial RDEB, and one with inversa RDEB. Forty-one mutations were identified, 18 of which are novel. Mutation consequences were analyzed at the mRNA and protein level and genotype-phenotype correlation was determined. Recessive inheritance of a new case of pretibial RDEB was also established. In RDEB patients, six recurrent mutations were identified: 7344G-->A, 425A-->G, 8441-14del21, 4783-1G-->A, 497insA, and G1664A, the last three being found only in Italian patients. Indeed, haplotype analysis supported propagation of ancestral mutated alleles within the Italian population for these particular mutations. Altogether recurrent mutations account for approximately 43% of RDEB alleles in Italian patients and therefore new DEB patients should first be screened for the presence of these mutations.
    Journal of Investigative Dermatology 12/2002; 119(6):1456-62. DOI:10.1046/j.1523-1747.2002.19606.x · 7.22 Impact Factor
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    ABSTRACT: Dystrophic epidermolysis bullosa (DEB) is a heritable mechanobullous skin disease derived from mutations in the type VII collagen gene (COL7A1). DEB cases are divided into dominant dystrophic EB (DDEB) and recessive dystrophic EB (RDEB). Most of the DDEB cases are induced by glycine substitution (GS) mutation because of its dominant negative effect, although there are silent GS which are not pathogenic without combination of other mutation in COL7Al. To know the relations between clinical features and COL7A1 mutations, we examined COL7A1 gene mutation in two Japanese families with DEB. one is dominantly inherited and another is sporadic. We identified three mutations; 8068de117ins2 in case L G2395D/152de1G in case 2. Case 1 is DDEB, which does not result from GS but from insertion/deletion mutation. In case 2, GS does not result in DDEB but causes recessive DEB (RDEB) with the combination of premature termination codon (PTC) in non-collagenous amino-terminal region (NC-l). This study demonstrates novel COL7A1 mutations for DEB and furthers our understanding of genotype-phenotype correlation displayed in DEB patients.
    Hirosaki Medical Journal 01/2007; 59(1).
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