Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI

Ullrich syndrome is a recessive congenital muscular dystrophy affecting con nective tissue and muscle. The molecular basis is unknown. Reverse transcri ption-PCR amplification performed on RNA extracted from fibroblasts or musc le of three Ullrich patients followed by heteroduplex analysis displayed he teroduplexes in one of the three genes coding for collagen type VI (COL6). In patient A, we detected a homozygous insertion of a C leading to a premat ure termination codon in the triple-helical domain of COL6A2 mRNA. Both hea lthy consanguineous parents were carriers. In patient B, we found a deletio n of 28 nucleotides because of an A --> G substitution at nucleotide -2 of intron 17 causing the activation of a cryptic acceptor site inside exon 18. The second mutation was an exon skipping because of a G --> A substitution at nucleotide -1 of intron 23, Both mutations are present in an affected b rother. The first mutation is also present in the healthy mother, whereas t he second mutation is carried by their healthy father. In patient C, we fou nd only one mutation so far-the same deletion of 28 nucleotides found in pa tient B. In this case, it was a de novo mutation, as it is absent in her pa rents. mRNA and protein analysis of patient B showed very low amounts of CO L6A2 mRNA and of COL6. A near total absence of COL6 was demonstrated by imm unofluorescence in fibroblasts and muscle. Our results demonstrate that Ull rich syndrome is caused by recessive mutations leading to a severe reductio n of COL6.