© 1995 Oxford University Press
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Pretibial epidermolysis bullosa: genetic linkage to COL7A1 and identification of a glycine-to-cysteine substitution in the triple-helical domain of type VII collagen
1Departments of Dermatology 2Biochemistry and Molecular Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University Philadelphia, PA, USA 3Department of Dermatology, National Cheng-Kung University Medical Center Taiwan 4Institute of Epidemiology, College of Public Health, National Taiwan University Taipei, Taiwan, ROC
*To whom correspondence be addressed
Received March 31, 1995; Accepted June 5, 1995
Pretibial epidermolysis bullosa (PEB) is a rare variant of dominant dystrophic EB (DDEB) in which recurrent blistering with scarring predominantly involves the pretibial skin. Although blistering appears to be localized clinically, electron microscopy of the dermal-epidermal junction in patients with PEB reveals anchoring fibril abnormalities that are not restricted to the predilection sites. Furthermore, PEB cannot be distinguished from the generalized (Cockayne-Touraine and Pasini) types of DDEB on the basis of anchoring fibril morphology alone. The generalized forms of DDEB have been linked to the type VII collagen gene (COL7A1) on chromosome 3p21. In this study, we sought to test the hypothesis that mutations underlying PEB also reside in COL7A1. We initiated mutational analysis in COL7A1 in a large five-generation PEB family of Taiwanese descent. We identified a G-to-T transversion at nt position 7867, which results in a glycine-to-cysteine substitution (G2623C) in exon 105. This mutation was confirmed in affected family members using the loss of a Sma\ restriction site, and when used for linkage analysis, together with an intragenic Pvull polymorphism and several flanking markers, resulted in a LOD score of Z = 3.61 at 
= 0 in this family. This is the first demonstration of genetic linkage and mutation analysis in PEB, and illustrates that the Cockayne-Touraine, Pasini, and now the pretibial clinical variants of DDEB are allelic, resulting from different glycine substitution mutations in the type VII collagen gene.
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