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Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy

Lookup NU author(s): Dr Debbie Hicks, Dr Steven Laval, Dr Anna Sarkozy, Elena Martoni, Professor Hanns Lochmuller, Emerita Professor Katherine Bushby, Professor Volker StraubORCiD


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Bethlem myopathy (BM) [MIM 158810] is a slowly progressive muscle disease characterized by contractures and proximal weakness, which can be caused by mutations in one of the collagen VI genes (COL6A1, COL6A2 and COL6A3). However, there may be additional causal genes to identify as in ∼50% of BM cases no mutations in the COL6 genes are identified. In a cohort of –24 patients with a BM-like phenotype, we first sequenced 12 candidate genes based on their function, including genes for known binding partners of collagen VI, and those enzymes involved in its correct post-translational modification, assembly and secretion. Proceeding to whole-exome sequencing (WES), we identified mutations in the COL12A1 gene, a member of the FACIT collagens (fibril-associated collagens with interrupted triple helices) in five individuals from two families. Both families showed dominant inheritance with a clinical phenotype resembling classical BM. Family 1 had a single-base substitution that led to the replacement of one glycine residue in the triple-helical domain, breaking the Gly-X-Y repeating pattern, and Family 2 had a missense mutation, which created a mutant protein with an unpaired cysteine residue. Abnormality at the protein level was confirmed in both families by the intracellular retention of collagen XII in patient dermal fibroblasts. The mutation in Family 2 leads to the up-regulation of genes associated with the unfolded protein response (UPR) pathway and swollen, dysmorphic rough-ER. We conclude that the spectrum of causative genes in extracellular matrix (ECM)-related myopathies be extended to include COL12A1.

Publication metadata

Author(s): Hicks D, Farsani G, Laval S, Collins J, Sarkozy A, Martoni E, Shah A, Zou Y, Koch M, Bönnemann C, Roberts M, Lochmüller H, Bushby K, Straub V

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2014

Volume: 23

Issue: 9

Pages: 2353-2363

Print publication date: 01/05/2014

Online publication date: 13/12/2013

Acceptance date: 10/12/2013

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddt637

PubMed id: 24334769


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