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Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy
Author(s) -
Vanegas Olga Camacho,
Zhang RuiZhu,
Sabatelli Patrizia,
Lattanzi Giovanna,
Bencivenga Paola,
Giusti Betti,
Columbaro Marta,
Chu MonLi,
Merlini Luciano,
Pepe Guglielmina
Publication year - 2002
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.10100
Subject(s) - collagen vi , exon , myopathy , mutation , microbiology and biotechnology , genetics , rna splicing , phenotype , biology , gene , rna
Bethlem myopathy is an early‐onset benign myopathy characterized by proximal muscular weakness and multiple flexion contractures. It is a dominantly inherited disorder associated with mutations in the three COL6 genes encoding type VI collagen. We detected a g→a substitution at +1 position of COL6A1 intron 3 in a four‐generation Italian family affected by a mild form of Bethlem myopathy. The mutation results in the activation of a cryptic splice donor site at the 3′ end of exon 3, leading to the loss of 66 nucleotides and an “in‐frame” deletion of 22 amino acids in the NH 2 ‐domain. Molecular analysis on fibroblasts of the propositus showed that the mutated mRNA was present and stable, but the mutated protein could not be detected. Western blot and immunofluorescence analyses showed a decreased level of collagen VI synthesis and deposition in fibroblasts of the propositus. Together, the results suggest that the mutated protein was highly unstable and rapidly degraded, and that the mild phenotype was caused by a reduced amount of normal collagen VI microfibrils. In addition, we demonstrated that lymphocytes can be used for the first mutation screening analysis of patients with Bethlem myopathy. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002