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.

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

“…Recently, various treatments were reported to restore the deficient proteins. These approaches fall mainly into three strategies: gene therapy (20)(21)(22)(23)(24), protein therapy (21,25,26), and cell therapy. Cell therapies using fibroblasts have been attempted for recessive dystrophic EB (RDEB) model mice and human patients, both of which lack collagen VII.…”

Eosinophil infiltration in three patients with generalized atrophic benign epidermolysis bullosa from a Japanese family: molecular genetic and immunohistochemical studies

“…Genetic analysis of the patients disclosed a novel, homozygous insertional mutation, 209-210insCA, in exon 5 of COL17A1. The insertion is located at the most 5¢-region among previously reported mutation sites (Bauer and Lanschuetzer 2003). The mutation is expected to create a premature termination codon in exon 9.…”

“…GABEB is caused by mutations in several genes, including those for collagen type XVII alpha-1 (COL17A1 mapped at 10q24.3), laminin gamma-2 (LAMC2 at 1q25-31), laminin beta-3 (LAMB3 at 1q32), and laminin alpha-3 (LAMA3 at 18q11.2). A number of truncation and missense mutations in COL17A1 have been reported (Schumann et al 1997;Bauer and Lanschuetzer 2003). The skin fragility of GABEB may be due to lack of the COL17A1 gene product (collagen XVII, also called BPAG2 or BP180).…”

Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay

“…The identification of the pathogenetic role of the exonic splice site paves the way for mutation-specific gene therapy using antisense oligonucleotides to block exonic splice site usage. 24,25 …”