A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the α1(VI) collagen chain in an Italian family affected by Bethlem myopathy

Guglielmina Pepe, Betti Giusti, Enrico Bertini, Tamara Brunelli, Biagio Saitta, Paolo Comeglio, Angela Bolognese, Luciano Merlini, Giorgio Federici, Rosanna Abbate, Mon Li Chu

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Abstract

Bethlem myopathy is a mild neuromuscular disorder with proximal muscular weakness and early flexion contractures. It is an autosomal dominant disease due to mutations in type VI collagen genes. We found a T→C substitution at the +2 position of COL6A1 intron 14 in a family, leading to skipping of exon 14 and an in-frame deletion of 18 amino acids in the triple-helical domain of the α1(VI) collagen chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to the protein secretion. Analysis of the affected fibroblasts showed that the shortened α1(VI) collagen chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggest that the clinical phenotype is due to a reduction in the level of type VI collagen in the extracellular matrix.

Original languageEnglish
Pages (from-to)802-807
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume258
Issue number3
DOIs
Publication statusPublished - May 19 1999

Fingerprint

Collagen Type VI
Collagen
Mutation
Microfibrils
Muscle Weakness
Contracture
Fibroblasts
Dimers
Introns
Extracellular Matrix
Cysteine
Exons
Substitution reactions
Genes
Phenotype
Amino Acids
Bethlem myopathy
Proteins

Keywords

  • Bethlem myopathy
  • COL6A1 gene
  • Collagen type VI
  • Neuromuscular disease

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the α1(VI) collagen chain in an Italian family affected by Bethlem myopathy. / Pepe, Guglielmina; Giusti, Betti; Bertini, Enrico; Brunelli, Tamara; Saitta, Biagio; Comeglio, Paolo; Bolognese, Angela; Merlini, Luciano; Federici, Giorgio; Abbate, Rosanna; Chu, Mon Li.

In: Biochemical and Biophysical Research Communications, Vol. 258, No. 3, 19.05.1999, p. 802-807.

Research output: Contribution to journalArticle

Pepe, Guglielmina ; Giusti, Betti ; Bertini, Enrico ; Brunelli, Tamara ; Saitta, Biagio ; Comeglio, Paolo ; Bolognese, Angela ; Merlini, Luciano ; Federici, Giorgio ; Abbate, Rosanna ; Chu, Mon Li. / A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the α1(VI) collagen chain in an Italian family affected by Bethlem myopathy. In: Biochemical and Biophysical Research Communications. 1999 ; Vol. 258, No. 3. pp. 802-807.
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AU - Bertini, Enrico

AU - Brunelli, Tamara

AU - Saitta, Biagio

AU - Comeglio, Paolo

AU - Bolognese, Angela

AU - Merlini, Luciano

AU - Federici, Giorgio

AU - Abbate, Rosanna

AU - Chu, Mon Li

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AB - Bethlem myopathy is a mild neuromuscular disorder with proximal muscular weakness and early flexion contractures. It is an autosomal dominant disease due to mutations in type VI collagen genes. We found a T→C substitution at the +2 position of COL6A1 intron 14 in a family, leading to skipping of exon 14 and an in-frame deletion of 18 amino acids in the triple-helical domain of the α1(VI) collagen chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to the protein secretion. Analysis of the affected fibroblasts showed that the shortened α1(VI) collagen chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggest that the clinical phenotype is due to a reduction in the level of type VI collagen in the extracellular matrix.

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