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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Varki
Roslyn
R
DebRA Molecular Diagnostics Laboratory, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Sadowski
Sara
S
Uitto
Jouni
J
Pfendner
Ellen
E
D000483:Alleles; D019943:Amino Acid Substitution; D024143:Collagen Type VII / Q000737:chemistry / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D004820:Epidermolysis Bullosa / Q000235:genetics; D016108:Epidermolysis Bullosa Dystrophica / Q000145:classification / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites / Q000235:genetics; D017422:Sequence Analysis, DNA
D024143:Collagen Type VII; D022821:RNA Splice Sites; D004247:DNA