Universität zu Köln

Hicks, Debbie, Farsani, Golara Torabi, Laval, Steven, Collins, James, Sarkozy, Anna, Martoni, Elena, Shah, Ashoke, Zou, Yaqun, Koch, Manuel ORCID: 0000-0002-2962-7814, Boennemann, Carsten G., Roberts, Mark, Lochmueller, Hanns, Bushby, Kate and Straub, Volker ORCID: 0000-0001-9046-3540 (2014). Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Hum. Mol. Genet., 23 (9). S. 2353 - 2364. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hicks, Debbie UNSPECIFIED UNSPECIFIED UNSPECIFIED Farsani, Golara Torabi UNSPECIFIED UNSPECIFIED UNSPECIFIED Laval, Steven UNSPECIFIED UNSPECIFIED UNSPECIFIED Collins, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Sarkozy, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Martoni, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Shah, Ashoke UNSPECIFIED UNSPECIFIED UNSPECIFIED Zou, Yaqun UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED orcid.org/0000-0002-2962-7814 UNSPECIFIED Boennemann, Carsten G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Roberts, Mark UNSPECIFIED UNSPECIFIED UNSPECIFIED Lochmueller, Hanns UNSPECIFIED UNSPECIFIED UNSPECIFIED Bushby, Kate UNSPECIFIED UNSPECIFIED UNSPECIFIED Straub, Volker UNSPECIFIED orcid.org/0000-0001-9046-3540 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-440025
DOI:	10.1093/hmg/ddt637
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	23
Number:	9
Page Range:	S. 2353 - 2364
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CONGENITAL MUSCULAR-DYSTROPHY; AUTOSOMAL-DOMINANT MYOPATHY; TENASCIN-X DEFICIENCY; BETHLEM MYOPATHY; SUPPORT OVERLAP; VI; DECORIN; DISEASE; CONTRACTURES; EXPRESSION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44002