The international dystrophic epidermolysis bullosa patient registry: An online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations

Abstract

Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype-phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling. We therefore constructed the International DEB Patient Registry (http://www.deb-central.org), aimed at worldwide collection and sharing of phenotypic and genotypic information on DEB. As of May 2011, this MOLGENIS-based registry contains detailed information on 508 published and 71 unpublished patients and their 388 unique COL7A1 mutations, and includes all combinations of mutations. The current registry RDEB versus DDEB ratio of 4:1, if compared to prevalence figures, suggests underreporting of DDEB in the literature. Thirty-eight percent of mutations stored introduce a premature termination codon (PTC) and 43% an amino acid change. Submission wizards allow users to quickly and easily share novel information. This registry will be of great help in disease diagnosing and genetic counseling and will lead to novel insights, especially in the rare phenotypes of which there is often lack of understanding. Altogether, this registry will greatly benefit the DEB patients.

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

“…More than 800 distinct mutations have been identified in RDEB patients, in which the prevalence of nonsense mutations in RDEB approaches 30% (32,33). Nonsense mutations result in PTCs that cause a truncated or unstable type VII collagen.…”

“…Our data may not reflect all potential responses in patients harboring other different nonsense mutations. It is important, however, to point out that 4 nonsense mutations studied here, R236X, R578X, R1683X, and R2814X, are recurrent mutations in RDEB patients and account for 8% of total RDEB patients and 25% of RDEB patients who have nonsense mutations (32,33).…”

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

“…19 In our patient, a somatic nucleotide change in the germline mutated codon rescues the mutant phenotype by reverting the nonsense codon to a tyrosine (p.X2170Tyr), which leads to the restoration of functionalproteinproduction.Theresultantmissensechange p.Gln2170Tyr has been described neither as a neutral polymorphism (dbSNP, http://www.ncbi.nlm.nih.gov/projects /SNP/) nor as a pathogenic mutation in patients with RDEB (International Dystrophic Epidermolysis Bullosa Patient Registry, www.deb-central.org, accessed on June 30, 2011). 20 This missense change resides at the third position of a Gly-X-Y triplet and, contrary to substitutions of glycine residues at the first position of the Gly-X-Y triples, 21 it is difficult, if not impossible, to predict the effect of such amino acid substitutions on triple-helix stability and clinical outcome. The pathogenicity prediction software pack- age Alamut, version 2.0 (Interactive Biosoftware, Rouen, France), classifies the p.Gln2170Tyr missense change as being of unknown pathogenicity.…”

Advances in understanding and treating dystrophic epidermolysis bullosa

“…Although TALEN correction appears to be a superior option to previous gene therapy methods, TALEN construction must be tailored to the particular COL7A1 loci that harbor the specific RDEB mutations, which can be both costly and labor-intensive [88]. As there are hundreds of causative mutations for RDEB characterized to date, using this approach on a larger scale may be challenging [89]. With the advent of clustered regulatory interspaced short palindromic repeats and associated proteins (CRISPR/Cas), the ability to correct multiple genetic mutations in human cells might have become considerably easier [90-92], although their off-target profile needs to be carefully analyzed [93].…”