Résumé :
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Communication n° 408 Ullrich congenital muscular dystrophy (UCMD) belongs to the subgroup of merosin-positive congenital muscular dystrophies. Early signs may be neonatal, such as arthrogryposis, torticollis, hip dislocation. It is characterized by a marked distal joint hyperlaxity especially at young age, associated with multiple joint contractures. UCMD is caused by a deficiency in collagen VI, a heterotrimeric extracellular matrix protein encoded by 3 large genes : COL6A1, COL6A2, and COL6A3. Homozygous or heterozygous compound mutations in these 3 genes cause complete or partial deficiency of COL6. A proportion of cases with moderate involvement are caused by de novo dominant negative mutations, thus limiting the interest of linkage analysis in small pedigrees. Fibroblasts were cultured from skin biopsies of numerous patients with UCMD phenotype with known or unknown collagen 6 deficiency in skeletal muscle. By immunohistochemistry the pattern of COL6 secretion was investigated often revealing partial or complete COL6 intra-cytoplasmic retention. In fibroblasts with a defect in COL6 secretion transcripts levels were investigated in a chain-specific quantitative RT-PCR assay. In some cases, a drastic reduction in the mRNA levels of only one chain was observed and sequencing of the corresponding coding sequence allowed the identification of disease-causing mutations. These mutations were nonsense mutations or frameshift mutations inducing mRNA degradation. Our results demonstrate the usefulness of mRNA quantification as a primary selection step in the identification of the mutant COL6 gene for patients harbouring mutations affecting mRNA stability.
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