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Collagen alpha-1(III) chain also known as alpha 1 chain of type III collagen is a protein that in humans is encoded by the COL3A1gene.[1][2] Three of these alpha 1 protein molecules, or chains, are required to form the type III collagen molecule which has a long triple-helical domain.
Type III collagen is synthesized by cells as a pre-procollagen.[3]
The signal peptide is cleaved off producing a procollagen molecule. Three identical type III procollagen chains come together in the carboxy-terminal ends, and the structure is stabilized by the formation of disulphide bonds. Each individual chain folds into left-handed triple-helix and the three chains are then wrapped together into a right-handed superhelix. Other post-translational modifications include removal of the large globular domains from both ends of the molecule by C- and N-proteinases to form type III collagen. In addition, some of the lysine residues are hydroxylated or glycosylated, and some lysine as well as hydroxylysine residues undergo oxidative deamination catalysed by lysyl oxidase. Crosslinking between certain lysine and hydroxylysine residues also occurs. In the extracellular space in tissues, type III collagen monomers assemble into macromolecular fibrils, which aggregate into fibers, providing a strong support structure for tissues requiring tensile strength.
The triple-helical conformation, which is a characteristic feature of all fibrillar collagens, is possible because of the presence of glycine as every third amino acid in the sequence of about 1000 amino acids. This (Gly-X-Y)n sequence is repeated 343 times in the type III collagen molecule. Proline or hydroxyproline is often found in the X- and Y-position giving the triple helix stability.
Tissue distribution
Type III collagen is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel.
Gene
The COL3A1 gene is located on the long (q) arm of chromosome 2 at 2q32.2, between positions 188,974,372 and 189,012,745. The gene has 51 exons and is approximately 40 kbp long.[4] COL3A1 gene is in tail-to-tail orientation with a gene for another fibrillar collagen, namely COL5A2.[4]
Two transcripts are generated from the gene using different polyadenylation sites. Although alternatively spliced transcripts have been detected for this gene, they are the result of mutations; these mutations alter RNA splicing, often leading to the exclusion of an exon or use of cryptic splice sites.[5][6][6] The resulting defective protein is the cause of a severe, rare disease, the vascular type of Ehlers-Danlos Syndrome (vEDS). These studies have also provided important information about RNA splicing mechanisms in multi-exon genes.
Clinical significance
Mutations in the COL3A1 gene cause the vascular type of Ehlers-Danlos syndrome (vEDS; also known as the EDS type IV; OMIM 130050). It is the most devastating form of EDS, since patients often die suddenly due to rupture of large arteries or other hollow organs.[7] Other clinical manifestations of vEDS include cigarette paper-like scarring of the skin, large ecchymoses over bony protuberances, skin so thin that subcutaneous vessels are readily visible, and joint laxity that is usually confined to fingers.[7]
A few patients with arterial aneurysms without clear signs of EDS have also been found to have COL3A1 mutations.[8][9][10]
The first single base mutation in the COL3A1 gene was reported in 1989 in a patient with vEDS and changing glycine amino acid to serine.[11] Since then, over 600 different mutations have been characterized in the COL3A1 gene.[12] About 2/3 of these mutations change a glycine amino acid to another amino acid in the triple-helical region of the protein chain.[7] A large number of RNA splicing mutations have also been identified.
It is difficult to predict the clinical severity based on the type and location of COL3A1 mutations. Several studies have reported on mosaicism, where one of the parents carries the mutation in some of her or his cells, but not in all cells, and appears phenotypically healthy, but has more than one affected offspring.[13]
Animal models
Inactivation of the murine Col3a1 gene led to a shorter life span in homozygous mutant mice. The mice died prematurely from a rupture of major arteries mimicking the human vEDS phenotype.[14]
↑Superti-Furga A, Gugler E, Gitzelmann R, Steinmann B (Jun 1988). "Ehlers-Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen". J Biol Chem. 263 (13): 6226–32. PMID2834369.
↑Kühn K. "The classical collagens: types I, II, and II". In Mayne R, Burgeson RE. Structure and function of collagen types. Academic Press. pp. 1–42. ISBN978-0-323-15571-7.
↑ 4.04.1Välkkilä M, Melkoniemi M, Kvist L, Kuivaniemi H, Tromp G, Ala-Kokko L (September 2001). "Genomic organization of the human COL3A1 and COL5A2 genes: COL5A2 has evolved differently than the other minor fibrillar collagen genes". Matrix Biology. 20 (5–6): 357–66. PMID11566270.
↑Kuivaniemi H, Kontusaari S, Tromp G, Zhao MJ, Sabol C, Prockop DJ (July 1990). "Identical G+1 to A mutations in three different introns of the type III procollagen gene (COL3A1) produce different patterns of RNA splicing in three variants of Ehlers-Danlos syndrome. IV. An explanation for exon skipping some mutations and not others". The Journal of Biological Chemistry. 265 (20): 12067–74. PMID2365710.
↑Anderson DW, Edwards TK, Ricketts MH, Kuivaniemi H, Tromp G, Stolle CA, Deak SB, Boyd CD (November 1996). "Multiple defects in type III collagen synthesis are associated with the pathogenesis of abdominal aortic aneurysms". Annals of the New York Academy of Sciences. 800: 216–28. PMID8958996.
↑Tromp G, Kuivaniemi H, Shikata H, Prockop DJ (January 1989). "A single base mutation that substitutes serine for glycine 790 of the alpha 1 (III) chain of type III procollagen exposes an arginine and causes Ehlers-Danlos syndrome IV". The Journal of Biological Chemistry. 264 (3): 1349–52. PMID2492273.
↑Dalgleish R. "COL3A1". Ehlers Danlos Syndrome Variant Database.
Kuivaniemi H, Tromp G, Prockop DJ (1997). "Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels". Hum. Mutat. 9 (4): 300–15. doi:10.1002/(SICI)1098-1004(1997)9:4<300::AID-HUMU2>3.0.CO;2-9. PMID9101290.
