Three homozygous PTC mutations in the collagen type VII gene of patients affected by recessive dystrophic epidermolysis bullosa: Analysis of transcript levels in dermal fibroblasts

The Hallopeau-Siemens variant of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a severe inherited skin disease characterized by the absence of collagen type VII (COLVII) and anchoring fibrils (AF), caused by mutatio ns in collagen type VT[ gene (COL7A1). Mutations leading to the formation o f premature termination codons (FTCs) of translation are the characteristic genetic lesions in HS-RDEB patients; many PTC mutations have been found to be associated with a marked reduction or complete absence of COLVII mRNA. In this article, we report homozygosity for three different mutations in th e COL7A1 of HS-RDEB patients, One mutation, the R2685X, falling in exon 109 , is a novel mutation, whereas the other two, the 425A-->G falling in exon 3 and the 497insA in exon 4, have been previously identified in compound he terozygosity with different mutations in other unrelated RDEB patients. Hap lotype analysis in three Italian families carrying the 497insA mutation sug gested a common origin of this mutation and indicated that this is an ances tral Italian mutation, All these mutations generate PTCs and are associated with the absence of COLVII expression, as detected by immunofluorescence a nalysis of the patient's skin. Evaluation of the levels of the mutated COLV II mRNAs in cultured skin fibroblasts of the patients and of their parents showed that all the mutated transcripts were expressed at consistent levels , Therefore, our results indicate that a marked mRNA reduction is not a con stant feature associated with PTC mutations in COL7A1. Hum Mutat 13:439-452 , 1999. (C) 1999 Wiley-Liss, Inc.