A Glycine-to-Arginine Substitution in the Triple-Helical Domain of Type VII Collagen in a Family with Dominant Dystrophic Epidermolysis Bullosa

Abstract

We recently demonstrated strong genetic linkage between the type VII collagen gene (COL7A1) and both the dominant and recessive forms of dystrophic epidermolysis bullosa. In this study, we searched for mutations in dominant dystrophic epidermolysis bullosa using polymerase chain reaction amplification of segments of COL7A1, followed by heteroduplex analysis. Examination of the polymerase chain reaction corresponding to exon 73 revealed a heteroduplex resulting from a G-to-A transition at nucleotide 6127 in the triple-helical domain of COL7A1, which converted a glycine residue to an arginine (G2043R). The dominant dystrophic epidermolysis bullosa phenotype in this family probably arose because of a dominant negative effect of this mutation in COL7A1, resulting in the formation of structurally abnormal anchoring fibrils.

Immunohistochemical, Ultrastructural, and Molecular Features of Kindler Syndrome Distinguish It From Dystrophic Epidermolysis Bullosa

“…Screening of the entire type VII collagen gene (COL7A1) in each alíele of both patients as well as their parents failed to detect any putative pathologic mutations. The sensitivity of this screening system de¬ tects more than 90% of the mutations occurring in COL7A1 ; therefore, the lack of any COL7A1 mutation in these patients suggests that Kindler syndrome is not a variant of dystrophic epidermolysis bullosa.34 36 Addi¬ tionally, the characteristic ultrastructural and immunohistochemical features found in Kindler syndrome fur¬ ther support the concept that Kindler syndrome is distinct from dystrophic epidermolysis bullosa, although both conditions have overlapping clinical features, including blister formation and fusion of the fingers and toes. Clinically, the present 2 cases appear to have slightly more scarring and webbing than those of previously reported Kindler The pathologic mechanism of the marked lamina densa duplication is unclear.…”

Review of collagen VII sequence variants found in Australasian patients with dystrophic epidermolysis bullosa reveals nine novel COL7A1 variants

“…However, EB98 results from the presence of a single G-C base substitution at nucleotide 6127 (or DNA nucleotide 23592) and EB213 has the same sequence variant in exon 73. G2043R has been identified as a result of a nucleotide change of G-A at position 6127 representing the first hotspot sequence variation to be elucidated in DDEB [25][26][27][28][29][30][31], however, the G to C base change has not been reported previously. G2043R is located in exon 73 which is highly conserved between the human, mouse and hamster (Fig.…”

COL7A1 mutation G2037E causes epidermal retention of type VII collagen

“…GS mutations on one allele have been found in many DDEB patients and in-frame deletion mutations have been observed for a few patients. Thus, COL7A1 GS mutations can cause both DDEB and RDEB subtypes (Christiano et al 1995;Shimizu et al 1996).…”