A novel missense mutation in the COL7A1 gene underlies epidermolysis bullosa pruriginosa

Abstract

Abbreviations: COL7A1, COL7A1 gene; DEB, dystrophic epidermolysis bullosa; DDEB, dominant dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; PCR, polymerase chain reaction. Keywords: COL7A1 gene, epidermolysis bullosa pruriginosa, mutation AbstractEpidermolysis bullosa (EB) pruriginosa is a subtype of dominant dystrophic epidermolysis bullosa (DDEB), characterized by severe pruritus and blistering localized to the extensor surface of the extremities. EB pruriginosa exhibits extensive clinical heterogeneity with variable expressivity and delayed age of onset. Mutations in the COL7A1 gene, especially in glycine residues within of Gly-X-Y repeats, have been shown to cause this form of DDEB. Here, we report a novel COL7A1 mutation in a Taiwanese pedigree with EB pruriginosa. Using polymerase chain reaction amplification and direct sequence analysis, we have identified a G-to-T transversion at nucleotide 7097 within exon 92 of COL7A1, converting a glycine residue to valine (G2366V). The mutation resides within a consecutive, uninterrupted 17 Gly-X-Y of the triple-helical domain of type VII collagen.Interestingly, the proband in our family also displayed elevated IgE levels, previously reported in some patients with this disorder. Our finding further implicates COL7A1 mutation in the pathogenesis of EB pruriginosa and underscores the heterogeneous clinical symptoms of glycine mutations in DDEB. Here, we have identified a two-generation EB pruriginosa kindred of Taiwanese descent (Fig. 1a). The proband is a 52-year old woman (II-8) who developed intense pruritic blisters in her lower extremities and extensor surface of both arms in her twenties. ReportA detailed clinical description of her symptoms was reported previously in the Chinese literature.13 Briefly, histology of biopsy showed a subepidermal cleft and mild perivascular mononuclear infiltration in the upper dermis. Upon electron microscopic examination, the anchoring fibrils were found to be decreased in number and thinner than in normal control skin. Neither the parents nor the six other siblings of the index case developed any similar symptoms. Recently, at the age of 25 years, the son (III-1) of the proband developed similar pruritic blisters on both shins and extensor arms (Fig. 2b).Although the 22 year-old daughter of the proband (III-2) lacked blistering lesions, nail dystrophy, and other symptoms of the disease, she had reported localized pruritus on pretibial skin and not yet reached the age of onset of her mother and brother.After obtaining informed consent, DNA was isolated from peripheral blood highlighting the importance of residue G2366 (Fig. 2). Similarly, a heterozygous glycineto-serine missense mutation (G2369S) in the adjacent Gly-X-Y repeat causes dominant EB pruriginosa (Fig. 2). 4 This observation is consistent with the notion that the specific position of a glycine substitution within a particular helical block, rather than its position along the entire collagenous domain, might be more critical in determining its impact on the ov...

<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.…”

New Glycine Substitution Mutations in Type VII Collagen Underlying Epidermolysis Bullosa Pruriginosa but the Phenotype is not Explained by a Common Polymorphism in the Matrix Metalloproteinase-1 Gene Promoter

“…The inheritance of EBP is usually autosomal dominant, but may be recessive in some cases (4,(6)(7)(8). Perhaps surprisingly, the nature ofthe pathogenic COL7AI mutations does not appear to differ from other forms of DEB (5)(6)(7)(9)(10)(11)(12)(13)(14)(15). Indeed, there are several examples of identical mutations in individuals from the same or different families resulting in either EBP or a more classical form of DEB (5,7,10,(13)(14)(15).…”

A novel missense mutation in COL7A1 in a Chinese pedigree with epidermolysis bullosa pruriginosa

“…EB pruriginosa is a rare clinical type of DEB, associated with intense pruritus and nodular prurigo-like lichenified lesions localized mostly on extensor surfaces of extremities [3]. Specifically in EB pruriginosa, most mutations of DEB reported in the literature involve glycine substitution, underlying both dominant and recessive forms of the disease [4].In this study, we describe a novel glycine substitution mutation in COL7A1 in a Chinese pedigree with dominant EB pruriginosa.The proband is a 23-year-old girl, from a fourgeneration family in which four members had similar cutaneous symptoms (Fig. …”

“…EB pruriginosa is a rare clinical type of DEB, associated with intense pruritus and nodular prurigo-like lichenified lesions localized mostly on extensor surfaces of extremities [3]. Specifically in EB pruriginosa, most mutations of DEB reported in the literature involve glycine substitution, underlying both dominant and recessive forms of the disease [4].…”