Collagen, type VI, alpha 3

COL6A3
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1KNT, 1KTH, 1KUN, 2KNT
Identifiers
Aliases	COL6A3 , DYT27, BTHLM1, UCMD1, collagen type VI alpha 3, collagen type VI alpha 3 chain
External IDs	OMIM: 120250 MGI: 88461 HomoloGene: 37917 GeneCards: COL6A3
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q37.3 Start 237,324,003 bp [1] End 237,414,328 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1 D|1 45.53 cM Start 90,765,923 bp [2] End 90,843,971 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium visceral pleura periodontal fiber synovial membrane synovial joint parietal pleura saphenous vein pericardium urethra tibia Top expressed in belly cord dermis calvaria cervix body of femur left lung lobe vas deferens ankle skin of back condyle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase inhibitor activity serine-type endopeptidase inhibitor activity extracellular matrix structural constituent conferring tensile strength Cellular component extracellular matrix extracellular vesicle collagen type VI trimer sarcolemma collagen endoplasmic reticulum lumen extracellular exosome extracellular space extracellular region collagen-containing extracellular matrix Biological process collagen catabolic process muscle organ development negative regulation of peptidase activity cell adhesion extracellular matrix organization negative regulation of endopeptidase activity growth plate cartilage chondrocyte morphogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1293 12835 Ensembl ENSG00000163359 ENSMUSG00000048126 UniProt P12111 n/a RefSeq (mRNA) NM_004369 NM_057164 NM_057165 NM_057166 NM_057167 NM_001243008 NM_001243009 NM_009935 RefSeq (protein) NP_004360 NP_476505 NP_476506 NP_476507 NP_476508 n/a Location (UCSC) Chr 2: 237.32 – 237.41 Mb Chr 1: 90.77 – 90.84 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Collagen alpha-3(VI) chain is a protein that in humans is encoded by the COL6A3 gene. ^{[5] [6] [7]} This protein is an alpha chain of type VI collagen that aids in microfibril formation. ^[8] 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. ^{[7] [9] [10]}

Structure

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. ^[7]

Function

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. ^[7] 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. ^[8]

Clinical significance

Mutations in the type VI collagen genes are associated with Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). ^{[7] [9]} 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. ^[9] A study on UCMD mutations by Zhang et al found only one non-pathogenic mutation in COL6A3. ^[10] 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. ^[9] Though high expression levels of COL6A3 have been correlated with obesity and diabetes in mice, this relationship was not observed in humans. ^[11] Other disorders involving muscle and connective tissue include weakness, joint laxity and contractures, and abnormal skin. ^[9]

References

1. GRCh38: Ensembl release 89: ENSG00000163359 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000048126 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. doi: 10.1016/S0021-9258(18)35949-0 . PMID   1339440.
6. Demir E, Sabatelli P, Allamand V, Ferreiro A, Moghadaszadeh B, Makrelouf M, Topaloglu H, Echenne B, Merlini L, Guicheney P (Jun 2002). "Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy". American Journal of Human Genetics. 70 (6): 1446–58. doi:10.1086/340608. PMC   419991 . PMID   11992252.
7. "Entrez Gene: COL6A3 collagen, type VI, alpha 3".
8. Lamandé 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 . PMID   16613849.
9. Bushby KM, Collins J, Hicks D (2014). "Collagen Type VI Myopathies". Progress in Heritable Soft Connective Tissue Diseases. Advances in Experimental Medicine and Biology. Vol. 802. pp. 185–99. doi:10.1007/978-94-007-7893-1_12. ISBN   978-94-007-7892-4. PMID   24443028.
10. Zhang 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. PMID   24801232. S2CID   38175712.
11. 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 . PMID   25337653.

Further reading

• Lampe AK, Bushby KM (Sep 2005). "Collagen VI related muscle disorders". Journal of Medical Genetics. 42 (9): 673–85. doi:10.1136/jmg.2002.002311. PMC   1736127 . PMID   16141002.
• Chu ML, Zhang RZ, Pan TC, Stokes D, Conway D, Kuo HJ, Glanville R, Mayer U, Mann K, Deutzmann R (Feb 1990). "Mosaic structure of globular domains in the human type VI collagen alpha 3 chain: similarity to von Willebrand factor, fibronectin, actin, salivary proteins and aprotinin type protease inhibitors". The EMBO Journal. 9 (2): 385–93. doi:10.1002/j.1460-2075.1990.tb08122.x. PMC   551678 . PMID   1689238.
• 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. doi: 10.1016/S0021-9258(18)37327-7 . PMID   3198591.
• Weil D, Mattei MG, Passage E, N'Guyen VC, Pribula-Conway D, Mann K, Deutzmann R, Timpl R, Chu ML (Mar 1988). "Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen". American Journal of Human Genetics. 42 (3): 435–45. PMC   1715162 . PMID   3348212.
• 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. 168 (2): 309–17. doi:10.1111/j.1432-1033.1987.tb13422.x. PMID   3665927.
• 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. PMID   7533217.
• 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. PMID   8387021.
• 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. PMID   8782832. S2CID   26173341.
• 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 . PMID   8805527.
• Myint E, Brown DJ, Ljubimov AV, Kyaw M, Kenney MC (Sep 1996). "Cleavage of human corneal type VI collagen alpha 3 chain by matrix metalloproteinase-2". Cornea. 15 (5): 490–6. doi:10.1097/00003226-199609000-00009. PMID   8862926.
• 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. PMID   9265624.
• 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 . PMID   9516440.
• Klewer SE, Krob SL, Kolker SJ, Kitten GT (Mar 1998). "Expression of type VI collagen in the developing mouse heart". Developmental Dynamics. 211 (3): 248–55. doi:10.1002/(SICI)1097-0177(199803)211:3<248::AID-AJA6>3.0.CO;2-H. PMID   9520112. S2CID   13299579.
• 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 . PMID   9536084.
• 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. PMID   11785962.
• 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. PMID   12011280. S2CID   36063361.
• 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. PMID   12077460.

External links

• GeneReviews/NCBI/NIH/UW entry on Congenital Muscular Dystrophy Overview