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Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes.

ABSTRACT: The dystrophic forms of epidermolysis bullosa (DEB), a group of heritable blistering disorders, show considerable phenotypic variability, and both autosomal dominant and autosomal recessive inheritance can be recognised. DEB is derived from mutations in the type VII collagen gene (COL7A1), encoding a large collagenous protein that is the predominant, if not exclusive, component of the anchoring fibrils at the dermal-epidermal junction.The Dystrophic Epidermolysis Bullosa Research Association Molecular Diagnostics Laboratory (Philadelphia, Pennsylvania, USA), established in 1996, has analysed more than 1000 families with different forms of epidermolysis bullosa, among them 332 families with DEB. DNA specimens were subjected to mutation analysis by polymerase chain reaction (PCR) amplification of all 118 exons and flanking intronic sequences of COL7A1, followed either by heteroduplex scanning and sequencing of the PCR products demonstrating heteroduplexes or by direct nucleotide sequencing.355 mutant alleles out of the anticipated 438 (81.1%) were disclosed. Among these mutations, a total of 242 mutations were distinct and 138 were novel, previously unreported mutations. No evidence of mutations in any other gene was obtained.Examination of the mutation database suggested phenotype-genotype correlations, contributing to the improved subclassification of DEB with prognostic implications. The mutation information also forms the basis for accurate genetic counselling and prenatal diagnosis in families at risk for recurrence.

SUBMITTER: Varki R

PROVIDER: S-EPMC2598021 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes.

Varki Roslyn R Sadowski Sara S Uitto Jouni J Pfendner Ellen E

Journal of medical genetics 20060913 3

<h4>Background</h4>The dystrophic forms of epidermolysis bullosa (DEB), a group of heritable blistering disorders, show considerable phenotypic variability, and both autosomal dominant and autosomal recessive inheritance can be recognised. DEB is derived from mutations in the type VII collagen gene (COL7A1), encoding a large collagenous protein that is the predominant, if not exclusive, component of the anchoring fibrils at the dermal-epidermal junction.<h4>Methods</h4>The Dystrophic Epidermolys ...[more]

PMID: 16971478

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Project description:BackgroundRecessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients.MethodsA double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions.ResultsBoth topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti-type VII collagen autoantibodies in patients' blood or skin.ConclusionTopical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations.Trial registrationClinicalTrials.gov NCT02698735.FundingEpidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH, and VA Merit Award.

Project description:Dystrophic epidermolysis bullosa, a severely disabling hereditary skin fragility disorder, is caused by mutations in the gene coding for collagen VII, a specialized adhesion component of the dermal-epidermal junction zone. Both recessive and dominant forms are known; the latter account for about 40% of cases. Patients with dominant dystrophic epidermolysis bullosa exhibit a spectrum of symptoms ranging from mild localized to generalized skin manifestations. Individuals with the same mutation can display substantial phenotypic variance, emphasizing the role of modifying genes in this disorder. The etiology of dystrophic epidermolysis bullosa has been known for around two decades; however, important pathogenetic questions such as involvement of modifier genes remain unanswered and a causative therapy has yet to be developed. Much of the failure to make progress in these areas is due to the lack of suitable animal models that capture all aspects of this complex monogenetic disorder. Here, we report the first rat model of dominant dystrophic epidermolysis bullosa. Affected rats carry a spontaneous glycine to aspartic acid substitution, p.G1867D, within the main structural domain of collagen VII. This confers dominant-negative interference of protein folding and decreases the stability of mutant collagen VII molecules and their polymers, the anchoring fibrils. The phenotype comprises fragile and blister-prone skin, scarring and nail dystrophy. The model recapitulates all signs of the human disease with complete penetrance. Homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene-dosage effect of mutated alleles in dystrophic epidermolysis bullosa. This novel viable and workable animal model for dominant dystrophic epidermolysis bullosa will be valuable for addressing molecular disease mechanisms, effects of modifying genes, and development of novel molecular therapies for patients with dominantly transmitted skin disease.

Dataset Information

Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes.

Publications

Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes.

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