Human COL6A1: Genomic characterization of the globular domains, structural and evolutionary comparison with COL6A2

Trikka, Dimitra; Davis, Terence; Lapenta, Vincenza; Brahe, Cristina Beate; Kessling, Anna M.

doi:10.1007/s003359900436

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Considering the high frequency of mutations affecting the COL6A2 C-domain, the rarity of UCMD/BM mutations involving the COL6A1 C-terminal region is intriguing, especially in view of the structural and evolutionary similarities between COL6A1 and COL6A2 genes, and thus far remains unexplained [22]. Based on their location in the same region of chromosome 21, it has been suggested that the two genes derive from a duplication of a primordial collagen VI gene; this hypothesis would explain the highly similar exon structure of their triple helical domains and the similar structure of α1(VI) and α2 (VI) chains [23].…”

Section: Discussionmentioning

confidence: 99%

“…Based on their location in the same region of chromosome 21, it has been suggested that the two genes derive from a duplication of a primordial collagen VI gene; this hypothesis would explain the highly similar exon structure of their triple helical domains and the similar structure of α1(VI) and α2 (VI) chains [23]. However, these genes differ in the region encoding the globular domains [22], and conservation in the C-terminus is limited to the region containing the cysteine residues essential for correct collagen assembly.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-Terminal domain: a case report

et al. 2013

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BackgroundMutations within the C-terminal region of the COL6A1 gene are only detected in Ullrich/Bethlem patients on extremely rare occasions.Case presentationHerein we report two Brazilian brothers with a classic Ullrich phenotype and compound heterozygous for two truncating mutations in COL6A1 gene, expected to result in the loss of the α1(VI) chain C2 subdomain. Despite the reduction in COL6A1 RNA level due to nonsense RNA decay, three truncated alpha1 (VI) chains were produced as protein variants encoded by different out-of-frame transcripts. Collagen VI matrix was severely decreased and intracellular protein retention evident.ConclusionThe altered deposition of the fibronectin network highlighted abnormal interactions of the mutated collagen VI, lacking the α1(VI) C2 domain, within the extracellular matrix, focusing further studies on the possible role played by collagen VI in fibronectin deposition and organization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-Terminal domain: a case report

et al. 2013

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“…To characterize the ␣1(VI) mRNA deletion, individual Bethlem myopathy RT-PCR products were cloned and sequenced. This analysis demonstrated that bases 1051-1104 (19), corresponding to sequences coded by COL6A1 exon 14 (15), were deleted from the mutant product (Fig. 3b).…”

Section: Bethlem Myopathy Fibroblasts Produce Structurallymentioning

confidence: 98%

Bethlem Myopathy and Engineered Collagen VI Triple Helical Deletions Prevent Intracellular Multimer Assembly and Protein Secretion

Lamandé¹,

Shields²,

Kornberg³

et al. 1999

Journal of Biological Chemistry

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Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, and COL6A3, are the cause of the autosomal dominant disorder, Bethlem myopathy. Although three different collagen VI structural mutations have previously been reported, the effect of these mutations on collagen VI assembly, structure, and function is currently unknown. We have characterized a new Bethlem myopathy mutation that results in skipping of COL6A1 exon 14 during pre-mRNA splicing and the deletion of 18 amino acids from the triple helical domain of the ␣1(VI) chain. Sequencing of genomic DNA identified a G to A transition in the ؉1 position of the splice donor site of intron 14 in one allele. The mutant ␣1(VI) chains associated intracellularly with ␣2(VI) and ␣3(VI) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted. This triple helical deletion thus resulted in production of half the normal amount of collagen VI. To further explore the biosynthetic consequences of collagen VI triple helical deletions, an ␣3(VI) cDNA expression construct containing a 202-amino acid deletion within the triple helix was produced and stably expressed in SaOS-2 cells. The transfected mutant ␣3(VI) chains associated with endogenous ␣1(VI) and ␣2(VI) to form collagen VI monomers, but dimers and tetramers did not form and the mutantcontaining molecules were not secreted. Thus, deletions within the triple helical region of both the ␣1(VI) and ␣3(VI) chains can prevent intracellular dimer and tetramer assembly and secretion. These results provide the first evidence of the biosynthetic consequences of structural collagen VI mutations and suggest that functional protein haploinsufficiency may be a common pathogenic mechanism in Bethlem myopathy.Bethlem myopathy is a mild dominantly inherited disorder characterized by early childhood onset of generalized muscle weakness and wasting and, commonly, contractures of multiple joints (1, 2). Mutations resulting in Bethlem myopathy have recently been identified in three genes, COL6A1, COL6A2, and COL6A3, that code for subunits of the extracellular matrix protein collagen VI (3-5). The constituent collagen VI chains, ␣1(VI), ␣2(VI), and ␣3(VI), each contain a central triple helixforming domain of repeating Gly-X-Y sequences, flanked by large N-and C-terminal regions primarily composed of ϳ200-amino acid subdomains that have homology to von Willibrand factor type A domains (6 -8). Stable collagen VI monomers are formed when the three chains associate intracellularly and assemble into disulfide-bonded helical heterotrimers (9). However, in contrast to other collagens, these molecules are not then secreted but assemble further within the cell into antiparallel overlapping dimers and then tetramers, which are stabilized by intermolecular disulfide bonds. Following secretion, tetramers link end-to-end to form characteristic beaded microfibrils (10, 11).Three of the described Bethlem myopathy mutations are glycine subs...

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“…COL6A3, the gene for the a3(VI) chain, maps to chromosome 2q37 59 (NT_005120). All three chains contain a central short triple helical domain of 335 to 336 amino acids with repeating Gly-Xaa-Yaa sequences, flanked by two large N-and C-terminal globular domains made up of motifs of 200 amino acids each, which are homologous to von Willebrand factor (vWF) type A domains [60][61][62][63][64] (fig 2). COL6A1, which consists of 37 exons (35 coding), contains one promoter 65 and produces a single transcript (NM_001848) encoding a protein of 1021 amino acids (NP_001839) with two C-terminal and one N-terminal vWF type A-like domains.…”

Section: Genomic Organisationmentioning

confidence: 99%

Collagen VI related muscle disorders

Lampe

Bushby²

2005

Journal of Medical Genetics

352

333

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Human COL6A1: Genomic characterization of the globular domains, structural and evolutionary comparison with COL6A2

Cited by 10 publications

References 19 publications

Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-Terminal domain: a case report

Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-Terminal domain: a case report

Bethlem Myopathy and Engineered Collagen VI Triple Helical Deletions Prevent Intracellular Multimer Assembly and Protein Secretion

Collagen VI related muscle disorders

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