Collagen alpha-3(VI) chain is a protein that in humans is encoded by the COL6A3gene. This protein is an alpha chain of type VI collagen that aids in microfibril formation. As part of type VI collagen, this protein has been implicated in Bethlem myopathy, Ullrich congenital muscular dystrophy (UCMD), and other diseases related to muscle and connective tissue.
This gene encodes the alpha 3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha 3 chain of type VI collagen is much larger than the alpha 1 and 2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, found in the amino terminal globular domain of all the alpha chains. In addition to the full length transcript, four transcript variants have been identified that encode proteins with N-terminal globular domains of varying sizes.
The alpha 3 type VI chain has been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Microfibril formation has been traced to interactions between its N-terminal subdomain N5 and its C-terminal C5 domain in adjacent type VI collagen monomers.
Mutations in the type VI collagen genes are associated with Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). Typically, both Bethlem myopathy and autosomal recessive UCMD patients are heterozygous for mutations in the three type VI collagen alpha chains, but only the former exhibit symptoms. Of the three alpha chains, COL6A3 mutations contribute to only 18% of the Bethlem myopathy and UCMD cases. A study on UCMD mutations by Zhang et al found only one non-pathogenic mutation in COL6A3. Nonetheless, knockdown of mutant COL6A3 in patient fibroblast cells using siRNA has successfully improved cellular deposition of type VI collagen in autosomal dominant UCMD, and may become a promising treatment for it.
Though high expression levels of COL6A3 have been correlated with obesity and diabetes in mice, this relationship was not observed in humans.
Other disorders involving muscle and connective tissue include weakness, joint laxity and contractures, and abnormal skin.
^Zanussi S, Doliana R, Segat D, Bonaldo P, Colombatti A (Nov 1992). "The human type VI collagen gene. mRNA and protein variants of the alpha 3 chain generated by alternative splicing of an additional 5-end exon". The Journal of Biological Chemistry. 267 (33): 24082–9. PMID1339440.
^ abLamandé SR, Mörgelin M, Adams NE, Selan C, Allen JM (Jun 2006). "The C5 domain of the collagen VI alpha3(VI) chain is critical for extracellular microfibril formation and is present in the extracellular matrix of cultured cells". The Journal of Biological Chemistry. 281 (24): 16607–14. doi:10.1074/jbc.M510192200. PMID16613849.
^ abZhang YZ, Zhao DH, Yang HP, Liu AJ, Chang XZ, Hong DJ, Bonnemann C, Yuan Y, Wu XR, Xiong H (May 2014). "Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy". World Journal of Pediatrics. 10 (2): 126–32. doi:10.1007/s12519-014-0481-1. PMID24801232.
^McCulloch LJ, Rawling TJ, Sjöholm K, Franck N, Dankel SN, Price EJ, Knight B, Liversedge NH, Mellgren G, Nystrom F, Carlsson LM, Kos K (Jan 2015). "COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity". Endocrinology. 156 (1): 134–46. doi:10.1210/en.2014-1042. PMID25337653.
Chu ML, Conway D, Pan TC, Baldwin C, Mann K, Deutzmann R, Timpl R (Dec 1988). "Amino acid sequence of the triple-helical domain of human collagen type VI". The Journal of Biological Chemistry. 263 (35): 18601–6. PMID3198591.
Chu ML, Mann K, Deutzmann R, Pribula-Conway D, Hsu-Chen CC, Bernard MP, Timpl R (Oct 1987). "Characterization of three constituent chains of collagen type VI by peptide sequences and cDNA clones". European Journal of Biochemistry / FEBS. 168 (2): 309–17. doi:10.1111/j.1432-1033.1987.tb13422.x. PMID3665927.
Arnoux B, Mérigeau K, Saludjian P, Norris F, Norris K, Bjørn S, Olsen O, Petersen L, Ducruix A (Mar 1995). "The 1.6 A structure of Kunitz-type domain from the alpha 3 chain of human type VI collagen". Journal of Molecular Biology. 246 (5): 609–17. doi:10.1016/S0022-2836(05)80110-X. PMID7533217.
Pfaff M, Aumailley M, Specks U, Knolle J, Zerwes HG, Timpl R (May 1993). "Integrin and Arg-Gly-Asp dependence of cell adhesion to the native and unfolded triple helix of collagen type VI". Experimental Cell Research. 206 (1): 167–76. doi:10.1006/excr.1993.1134. PMID8387021.
Jöbsis GJ, Keizers H, Vreijling JP, de Visser M, Speer MC, Wolterman RA, Baas F, Bolhuis PA (Sep 1996). "Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures". Nature Genetics. 14 (1): 113–5. doi:10.1038/ng0996-113. PMID8782832.
Zweckstetter M, Czisch M, Mayer U, Chu ML, Zinth W, Timpl R, Holak TA (Feb 1996). "Structure and multiple conformations of the kunitz-type domain from human type VI collagen alpha3(VI) chain in solution". Structure. 4 (2): 195–209. doi:10.1016/S0969-2126(96)00022-6. PMID8805527.
Sorensen MD, Bjorn S, Norris K, Olsen O, Petersen L, James TL, Led JJ (Aug 1997). "Solution structure and backbone dynamics of the human alpha3-chain type VI collagen C-terminal Kunitz domain,". Biochemistry. 36 (34): 10439–50. doi:10.1021/bi9705570. PMID9265624.
Lamandé SR, Sigalas E, Pan TC, Chu ML, Dziadek M, Timpl R, Bateman JF (Mar 1998). "The role of the alpha3(VI) chain in collagen VI assembly. Expression of an alpha3(VI) chain lacking N-terminal modules N10-N7 restores collagen VI assembly, secretion, and matrix deposition in an alpha3(VI)-deficient cell line". The Journal of Biological Chemistry. 273 (13): 7423–30. doi:10.1074/jbc.273.13.7423. PMID9516440.
Pan TC, Zhang RZ, Pericak-Vance MA, Tandan R, Fries T, Stajich JM, Viles K, Vance JM, Chu ML, Speer MC (May 1998). "Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy". Human Molecular Genetics. 7 (5): 807–12. doi:10.1093/hmg/7.5.807. PMID9536084.
Aigner T, Hambach L, Söder S, Schlötzer-Schrehardt U, Pöschl E (Jan 2002). "The C5 domain of Col6A3 is cleaved off from the Col6 fibrils immediately after secretion". Biochemical and Biophysical Research Communications. 290 (2): 743–8. doi:10.1006/bbrc.2001.6227. PMID11785962.
Mercuri E, Yuva Y, Brown SC, Brockington M, Kinali M, Jungbluth H, Feng L, Sewry CA, Muntoni F (May 2002). "Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study". Neurology. 58 (9): 1354–9. doi:10.1212/wnl.58.9.1354. PMID12011280.
Arnoux B, Ducruix A, Prangé T (Jul 2002). "Anisotropic behaviour of the C-terminal Kunitz-type domain of the alpha3 chain of human type VI collagen at atomic resolution (0.9 A)". Acta Crystallographica Section D. 58 (Pt 7): 1252–4. doi:10.1107/S0907444902007333. PMID12077460.