title: Type XVII collagen gene mutations in junctional epidermolysis bullosa and prospects for gene therapy.
abstract: Non-Herlitz junctional epidermolysis bullosa (nH-JEB) is caused predominantly by mutations leading to premature stop codons on both alleles of the type XVII collagen gene (COL17A1). The analysis of mutations in this gene has provided a means of correlating genotype with phenotype of nH-JEB patients. The phenotype of nH-JEB is characterized by generalized blistering of skin and mucous membranes with atrophic scarring and nail dystrophy. Atrophic alopecia is a distinct feature of nH-JEB patients, but one that is not associated with the severity of the disease at other sites. Enamel hypoplasia and pitting of the teeth are also characteristic for nH-JEB and can be used to facilitate the correct diagnosis in children with a blistering skin disease. Analysis of the biological consequences of mutations in the COL17A1 gene has shown that most patients lack type XVII collagen mRNA due to nonsense-mediated mRNA decay. Patients with these mutations can therefore be a target for corrective gene therapy using vectors coding for full-length type XVII collagen. Proof of principle for this approach has recently been demonstrated. The analysis of naturally occurring phenomena of gene correction in the COL17A1 gene provides evidence for other mechanisms of gene correction in genetic diseases. For example, exclusion of an exon carrying a mutation can lead to a milder phenotype of nH-JEB than predicted by the original mutation. In addition, we have gained data suggesting that COL17A1 exons harbouring pathogenic mutations can also be repaired by trans-splicing, i.e. aligning corrected RNA sequences to introns in the vicinity of faulty exons in the COL17A1 premtRNA.
authors.affiliation: Department of Dermatology, General Hospital Salzburg, Austria. jo.bauer@lks.at
authors.forename: J W
authors.initials: JW
authors.lastname: Bauer
authors.forename: C
authors.initials: C
authors.lastname: Lanschuetzer
mesh_terms: D000505:Alopecia / Q000235:genetics; D001324:Autoantigens / Q000235:genetics*; D002352:Carrier Proteins; D003094:Collagen / Q000235:genetics*; D003598:Cytoskeletal Proteins; D003744:Dental Enamel Hypoplasia / Q000235:genetics; D000071821:Dystonin; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D002352:Carrier Proteins; D003094:Collagen; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C486268:DST protein, human