Dominant Dystrophic Epidermolysis Bullosa Pruriginosa Research Articles

A case of dominant dystrophic epidermolysis bullosa pruriginosa with a novel mutation in the hinge region of COL7A1

A case of dominant dystrophic epidermolysis bullosa pruriginosa with a novel mutation in the hinge region of COL7A1

Dominant dystrophic epidermolysis bullosa pruriginosa with the G2287R mutation

ejd.2012.1799 Auteur(s) : Moyu Yajima1, Akihiko Kitoh1, Hajime Nakano2, Daisuke Sawamura2, Yoshiki Miyachi1, Kenji Kabashima1 kaba@kuhp.kyoto-u.ac.jp 1 Department of Dermatology, Kyoto School of Medicine, 54 ShogoinnKawara Sakyo, Kyoto 606-8507, Japan 2 Department of Dermatology, Hirosaki School of Medicine, Aomori 036-8216, Japan Dominant dystrophic epidermolysis bullosa pruriginosa (DDEB-pr) is a variant of dystrophic epidermolysis bullosa (DEB) characterized by severe pruritus and scarring, predominantly involving [...]

Case of dominant dystrophic epidermolysis bullosa pruriginosa with a c.7868G>A (G2623D) mutation in type VII collagen

Case of dominant dystrophic epidermolysis bullosa pruriginosa with a c.7868<scp>G</scp>&gt;<scp>A</scp> (<scp>G</scp>2623<scp>D</scp>) mutation in type <scp>VII</scp> collagen

Genotype–Phenotype Correlation in Chinese Patients with Dystrophic Epidermolysis Bullosa Pruriginosa

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare variant of dystrophic epidermolysis bullosa (DEB) due to dominant or recessive mutations in the COL7A1 gene. More than 40 mutations in COL7A1 have been described in DEB-Pr. The aim of this study was to understand the genotype-phenotype correlation in Chinese patients with DEB-Pr. Three Chinese families with typical clinical features of DEB-Pr were studied. The results were analysed in association with the eight Chinese DEB-Pr patients reported in the literature. In the three Chinese families with DEB-Pr, we found two dominant cases with G1773R and c.6900+1G>C mutations, and one case with heterozygous G2701W mutation of uncertain inheritance mode. In the 10 Chinese patients with dominant type of DEB-Pr, 7 glycine substitutions and three splicing site mutations of exon 87 skipping were identified. Glycine substitution mutations in the triple helix region and exon 87 skipping, leading to the in-frame deletion of 23 amino acid residues in the triple-helix, are often seen in Chinese patients with dominant DEB-Pr, although the glycine substitutions are also frequently present in dominant DEB.

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

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) (OMIM 604129) represents a distinct variant within the DEB clinical spectrum. 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. DEB-Pr is caused by either dominant (DDEB-Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII). 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. 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.

Exon 87 skipping of the COL7A1 gene in dominant dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is a rare, inherited, blistering disorder resulting from mutations in the COL7A1 gene, which encodes the anchoring fibrils, type VII collagen. We herein describe a further Japanese girl diagnosed with dominant DEB (DDEB). She had blisters sporadically and erosions healed with mild scarring and milia on the knees and pretibial regions. Severe pruritus was present at this time. Direct nucleotide sequencing of genomic DNA disclosed a heterozygous same splice-site mutation c.6900G>A in the COL7A1, which causes in-frame exon 87 skipping. So far, five different COL7A1 mutations leading to exon 87 skipping have been identified in rare forms of DEB: four DDEB pruriginosa and one pretibial DDEB. Therefore, a recent study suggested that exon 87 skipping in COL7A1 was related to the phenotype of DDEB pruriginosa. When she was 18 years old, however, the blister formation and pruritus markedly decreased. Therefore, her clinical symptoms were consistent to very mild DDEB but not to DDEB pruriginosa. Taken together, in-frame exon 87 skipping through c.6900G>A mutation may account for the mild skin features, rather than DDEB pruriginosa, in the present case.

Dystrophic epidermolysis bullosa pruriginosa in Italy: clinical and molecular characterization

Dystrophic epidermolysis bullosa (DEB) pruriginosa (DEB-Pr) is a rare variant of DEB due to COL7A1 dominant and recessive mutations, which is characterized by severe itching and lichenoid or nodular prurigo-like lesions, mainly involving the extremities. Less than 30 patients have been described showing variable disease expression, and frequently, delayed age of onset. We report the clinical and molecular characterization of seven Italian DEB patients, three affected with recessive DEB-Pr and four with dominant DEB-Pr. In all the patients, the signs were typical of a mild DEB phenotype, until the onset of pruritus, which was followed by worsening of the clinical picture, with appearance of the distinctive lichenified lesions of DEB-Pr. Nine mutations were found in the COL7A1 gene, three of which were novel and one was de novo. DEB-Pr patients with either dominant or recessive mutations were shown to synthesize a normal or variably reduced amount of type VII collagen, which was correctly deposited at the dermal-epidermal junction. Since six of these mutations have been reported in DEB patients in the absence of intense pruritus, these data implicate a role of yet unidentified phenotype-modifying factors in the pathogenesis of DEB-Pr.

Thalidomide in the management of epidermolysis bullosa pruriginosa

Epidermolysis bullosa (EB) pruriginosa is a distinctive clinical subtype of dystrophic EB. We report a patient with dominant dystrophic EB pruriginosa, who had an excellent response to systemic thalidomide treatment. The mechanism of action of thalidomide in the management of pruriginous disorders is not yet completely understood. Most recent studies point towards an immunomodulatory action of thalidomide that may suppress excessive production of tumour necrosis factor-alpha and may downregulate certain cell surface adhesion molecules involved in leucocyte migration.

A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa.

Dystrophic epidermolysis bullosa pruriginosa, a subtype of epidermolysis bullosa dystrophica and a heterogeneous inherited disease, is characterized by pruritus, excoriated nodular prurigo-like lesions, skin fragility, altered anchoring fibrils and loss of dermal-epidermal adhesion. Mutation in type VII collagen gene (COL7A1) is thought to be implicated in the underlying change for dystrophic epidermolysis bullosa pruriginosa. We report here a large family of dominant dystrophic epidermolysis bullosa pruriginosa. Mutation analysis using polymerase chain reaction and direct sequencing demonstrated a novel nucleotide substitution of 6899A-->G in exon 87 in one COL7A1 allele of the proband and 18 affected family members. This substitution was not found in 100 normal alleles. Polymerase chain reaction and sequencing of the cDNA, reverse transcribed from the proband's peripheral lymphocyte RNA, suggest that this mutation causes aberrant COL7A1 mRNA splicing of exon 87 skipping. Clinical features and pedigree analysis suggest that 6899A-->G substitution is a mutation with full penetrance and variable expressivity.

A Glycine-to-Arginine Substitution in the Triple-Helical Domain of Type VII Collagen in a Family with Dominant Dystrophic Epidermolysis Bullosa Pruriginosa

Epidermolysis bullosa pruriginosa is a recently recognized variant of dystrophic epidermolysis bullosa (DEB) characterized by severe pruritus and scarring, mainly involving the extensors of the extremities. In this study, we searched for mutations in the type VII collagen gene (COL7A1) using polymerase chain reaction amplification of exonic segments of COL7A1, followed by heteroduplex analysis, in a Chinese pedigree with dominant DEB displaying a striking anastomosing network of lichenoid papules and scarring. The study revealed a G-to-A transition at nucleotide 6724 within exon 85 of COL7A1, converting a glycine to an arginine (G2242R) within the triple-helical domain of the type VII collagen in affected individuals. These findings demonstrate that EB pruriginosa in this family is a clinical variant of dominant DEB.