Collagen type VI is a widespread heterotrimeric extracellular matrix glycoprotein; it is mainly present in the stroma, but it also forms a microfibrillar network in close association with the basement membrane of most tissues [1].
Its subunits, the α1(VI), α2(VI), and α3(VI) chains, are encoded by the COL6A1, COL6A2 (chr.21q22.3) [2, 3] and COL6A3 (chr.2q37) [3] genes respectively and share a central triple-helix (TH) domain with repeating Gly-Xaa-Yaa sequences flanked by N- and C-globular domains [4–6].
Formation of collagen VI is a complex multi-step process: inside the cells, the equimolar association of the three subunits to form a triple-helical monomer is followed by assembly into disulphide-bonded anti-parallel dimers, which then align to form tetramers, also stabilized by disulphide bonds. Outside the cell, the tetramers, the secreted form of collagen VI, associate end-to-end through overlapping N-terminal globular domains, thereby forming double-beaded microfibrils [1].
Mutations in the COL6A1, COL6A2, and COL6A3 genes cause collagen VI-related myopathies, a group of allelic disorders exhibiting a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise [7–9].
Ullrich congenital muscular dystrophy (UCMD, OMIM #254090), caused by both inherited recessive and dominant de novo COL6 mutations, is the most severe of these disorders. In UCMD patients, collagen VI is typically reduced or absent in the muscle and in cultured skin fibroblasts [10–12]. The majority of COL6 gene mutations reported in UCMD patients result in premature termination codons [7,8; Leiden Muscular Dystrophy pages http://www.dmd.nl/col6a1, http://www.dmd.nl/col6a2, and http://www.dmd.nl/col6a3]. In addition, missense mutations substituting glycine in the TH Gly-Xaa-Yaa motif are frequently reported [7, 8, 13], as well as splicing mutations leading to in-frame exon deletions [7, 8, 14].
Although clear mutational hot spots have not been identified, exon 10 of COL6A1, exon 26 of COL6A2 and intron 16 of COL6A3 seems to be preferentially mutated [8] and the topographical distribution of mutations along the different protein domains differs between the chains. In the α2(VI) chain, mutations have been described affecting N-terminal, TH and C-terminal domains to a similar degree. In contrast, mutations in α1(VI) and α3(VI) chains are almost exclusively located in the TH and N-terminal domains, with just few in frame deletions and missense changes affecting the C-terminal regions have been described and in general mutations in these C-domains being very rare [8; Leiden Muscular Dystrophy pages http://www.dmd.nl/col6a1, http://www.dmd.nl/col6a2 and http://www.dmd.nl/col6a3]. Indeed, no truncating mutations have been described in this domain of the α3(VI) chain, and only one case of UCMD carrying a homozygous truncating mutation within the a1(VI) chain C-terminus has been reported [15].
In this study we characterize the clinical, transcriptional, immunohistochemical and biochemical features of a rare example of truncating mutations within the C-terminal domain of the COL6A1 gene, detected in two Brazilian brothers with UCMD.