Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency |
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Authors: | Lamande SR; Bateman JF; Hutchison W; McKinlay Gardner RJ; Bower SP; Byrne E; Dahl HH |
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Institution: | Orthopaedic Molecular Biology Research Unit, Department of Paediatrics, University of Melbourne and Murdoch Institute, Royal Children's Hospital, Parkville 3052, Australia. lamandes@cryptic.rch.unimelb.edu.au |
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Abstract: | We have identified a new pathogenic mechanism for an inherited muscular
dystrophy in which functional haploinsufficiency of the extracellular
matrix protein collagen VI causes Bethlem myopathy. The heterozygous COL6A1
mutation results in a single base deletion from the mRNA and a premature
stop codon. The mutant mRNA is unstable, subject to nonsense- mediated mRNA
decay, and is almost completely absent both from patient fibroblasts and
skeletal muscle, resulting in haploinsufficiency of the alpha1(VI) subunit
and reduced production of structurally normal collagen VI. This is the
first example of a muscular dystrophy caused by haploinsufficiency of a
structural protein or member of the dystrophin-glycoprotein complex, and
identifies collagen VI as a critical contributor to cell-matrix adhesion in
skeletal muscle.
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