Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy

Muscle & Nerve
Olga Camacho VanegasGuglielmina Pepe

Abstract

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 NH2-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.

References

Mar 1, 1976·Brain : a Journal of Neurology·J Bethlem, G K Wijngaarden
Aug 1, 1996·Developmental Dynamics : an Official Publication of the American Association of Anatomists·D MarvulliG M Bressan
Aug 7, 1998·Human Heredity·T C PanM L Chu
Jun 21, 2001·Proceedings of the National Academy of Sciences of the United States of America·O Camacho VanegasG Pepe

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Citations

Sep 18, 2003·Brain & Development·Asuri N Prasad, Chitra Prasad
Jun 22, 2011·Nature Reviews. Neurology·Carsten G Bönnemann
Mar 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Luciano MerliniPaolo Bernardi
Oct 25, 2003·Nucleic Acids Research·Xavier RocaAdrian R Krainer
Sep 1, 2002·Journal of Clinical Neuromuscular Disease·Cameron R AdamsStefan-M Pulst
Jan 20, 2005·Histopathology·D S Tews, H H Goebel
Sep 6, 2005·Journal of Medical Genetics·A K Lampe, K M D Bushby
Jul 26, 2005·The International Journal of Neuroscience·Arun Aggarwal, Garth Nicholson
Nov 15, 2011·Neuromuscular Disorders : NMD·J KimF Muntoni
Nov 14, 2006·Biochimica Et Biophysica Acta·Matthew T Lisi, Ronald D Cohn
Aug 24, 2017·Journal of Clinical Neurology·Jung Hwan LeeYoung Chul Choi

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