Genetic studies of 20 Japanese families of dystrophic epidermolysis bullosa

Abstract

Dystrophic EB (DEB) is clinically characterized by mucocutaneous blistering in response to minor trauma, followed by scarring and nail dystrophy, and is caused by mutations in the COL7A1 gene encoding type VII collagen. DEB is inherited in either an autosomal dominant (DDEB) or recessive (RDEB) fashion. DDEB basically results from a glycine substitution mutation within the collagenous domain on one COL7A1 allele, while a combination of mutations such as premature stop codon, missense, and splice-site mutations on both alleles causes RDEB. In this study, mutation analysis was performed in 20 distinct Japanese DEB families (16 RDEB and four DDEB). The result demonstrated 30 pathogenic COL7A1 mutations with 16 novel mutations, which included four missense, five nonsense, one deletion, two insertion, one indel, and three splice-site mutations. We confirmed that Japanese COL7A1 mutations were basically family specific, although three mutations, 5818delC, 6573+1G>C, and E2857X, were recurrent based on previous reports. Furthermore, the Q2827X mutation found in two unrelated families would be regarded as a candidate recurrent Japanese COL7A1 mutation. The study furthers our understanding of both the clinical and allelic heterogeneity displayed in Japanese DEB patients.

Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation

“…Approximately 300 distinct COL7A1 mutations have been identified in patients with DEB around the world, and the clinical features, severity, prognosis, and response to treatment vary depending on the specific mutation. 15,24,[27][28][29][30][31] Our understanding of how specific mutations produce differing clinical presentations and prognoses is limited. We believe that our systems have the advantage of being able to use human genes.…”

“…Interestingly, the COL7 mϪ/Ϫ, K14-⌬hϩ mice gradually developed the DEB phenotype, including nail dystrophy, scarring on the paws, fusion of the digits, yellowish dental caries, and mild alopecia, characteristic features of human RDEB ( Figure 5, K-O). [13][14][15] It was difficult to distinguish the alopecia seen in the COL7 mϪ/Ϫ, K14-⌬hϩ mice from barbarism only from clinical appearance. However, the penetration of the alopecia is almost 100% in the COL7 mϪ/Ϫ, K14-⌬hϩ mice, whereas only a few wild-type littermates that were kept in the same condition showed barbarism.…”

<i>COL7A1</i> Recessive Mutations in Two Siblings with Distinct Subtypes of Dystrophic Epidermolysis Bullosa: Pruriginosa versus Nails Only

“…The p.G2366A mutation interrupts a continuous stretch of 16 Gly-X-Y repeats within the collagenous domain of COLVII, but its damaging effect on triple helix assembly is not evident at the heterozygous state [10]. Two similar mutations, p.G2366S and p.G2366C, resulted in mild recessive DEB forms when combined with other mutations in the second allele, but another change in the same codon, p.G2366V, caused dominant EBP [11,12,13]. In the latter family, however, disease onset occurred during the twenties in 2 subjects while an additional heterozygous carrier of the mutation lacked DEB symptoms.…”

COL7A1 mutation G2037E causes epidermal retention of type VII collagen

“…During the course of COL7A1 DEB patient mutational analysis (Sawamura et al 2005) we found a unique GS mutation which was associated with retention of type VII collagen in keratinocytes. Some, but not all, GS COL7A1 mutations result in intracellular accumulation of collagen VII (Hammami-Hauasli et al 1998;Shimizu et al 1999).…”