Collagen, type IV, alpha 1 explained

Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13.^{[1] [2]} It is ubiquitously expressed in many tissues and cell types.^[3] COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis.^[4] Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The COL4A1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

Structure

Gene

The COL4A1 gene resides on chromosome 13 at the band 13q34 and contains 54 exons.[5] This gene produces 2 isoforms through alternative splicing.^[5]

Protein

COL4A1 belongs to the type IV collagen family and contains three domains: a short N-terminal domain, a long triple-helical 7S domain at its center, and a non-collagenous 1 (NC1) domain at its C-terminal.^[6] The triple-helical domain contains interrupted G-X-Y repeats, which is suspected to allow flexibility of the domain. The NC1 domain is composed of two trimeric caps, each containing two alpha 1 fragments and one alpha 2 fragment, that form a sixfold propeller arranged around an axial tunnel. The interaction between these two caps occurs along a large planar interface and is stabilized by a covalent cross-link between the alpha 1 and alpha 2 chains across the two caps.

Function

Type IV collagen is the major structural component of basement membranes, which contains two or three COL4A1 proteins.^[7] Thus, COL4A1 is abundant and found in all types of basement membranes.^[8] The NC1 domain of COL4A1 is an important antiangiogenic molecule to control the formation of new capillaries.^[9] NC1 binds to the α1β1 integrin and inhibits specific integrin signaling pathways in vascular epithelial cells. It also regulates HIF-1α and VEGF expression, presumably by inhibiting the MAPK signaling cascade. These findings may explain the antitumorigenic function of NC1.^[10]

Clinical significance

Mutations in COL4A1 exons 24 and 25 are associated with HANAC (autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps).^[11] It has also been confirmed that mutations in the COL4A1 gene occur in some patients with porencephaly and schizencephaly.^{[12] [13]}

In humans, a novel mutation of the COL4A1 gene coding for collagen type IV was found to be associated with autosomal dominant congenital cataract in a Chinese family. This mutation was not found in unaffected family members or in 200 unrelated controls. In this study, sequence analysis confirmed that the Gly782 amino acid residue was highly conserved.^[14] This report of a new mutation in the COL4A1 gene is the first report of a non-syndromic autosomal dominant congenital cataract that highlights an important role for collagen type IV in the physiological and optical properties of the lens.^[14]

Additionally, in the cardiovascular field, the COL4A1 and COL4A2 regions on chromosome 13q34 are a highly replicated locus for coronary artery disease. In a normal wall of arteries, collagen type IV acts to inhibit smooth muscle cell proliferation. Accordingly, it was demonstrated that protein expression of collagen type IV in human vascular smooth muscle cells is regulated by both SMAD3 protein and TGFβ mediated stimulation of mRNA.^[15] Altogether, it was concluded that the pathogenesis of coronary artery disease may be regulated by COL4A1 and COL4A2 genes.^[15]

An autosomal recessive encephalopathy associated with mutations in this gene has also been reported.^[16]

Clinical Marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the COL4A1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).^[17]

Further reading

• Tryggvason K, Soininen R, Hostikka SL, Ganguly A, Huotari M, Prockop DJ . Structure of the human type IV collagen genes . Annals of the New York Academy of Sciences . 580 . 97–111 . 1990 . 1 . 2186699 . 10.1111/j.1749-6632.1990.tb17922.x . 1990NYASA.580...97T . 44878809 .
• Hinek A . Nature and the multiple functions of the 67-kD elastin-/laminin binding protein . Cell Adhesion and Communication . 2 . 3 . 185–93 . July 1994 . 7827955 . 10.3109/15419069409004436 .
• Ständer M, Naumann U, Wick W, Weller M . Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth . Cell and Tissue Research . 296 . 2 . 221–7 . May 1999 . 10382266 . 10.1007/s004410051283 . 20282995 .
• Kurpakus Wheater M, Kernacki KA, Hazlett LD . Corneal cell proteins and ocular surface pathology . Biotechnic & Histochemistry . 74 . 3 . 146–59 . May 1999 . 10416788 . 10.3109/10520299909047967 .
• Ghebrehiwet B, Peerschke EI, Hong Y, Munoz P, Gorevic PD . Short amino acid sequences derived from C1q receptor (C1q-R) show homology with the alpha chains of fibronectin and vitronectin receptors and collagen type IV . Journal of Leukocyte Biology . 51 . 6 . 546–56 . June 1992 . 1377218 . 10.1002/jlb.51.6.546. 1214598 .
• Gupta S, Batchu RB, Datta K . Purification, partial characterization of rat kidney hyaluronic acid binding protein and its localization on the cell surface . European Journal of Cell Biology . 56 . 1 . 58–67 . October 1991 . 1724753 .
• Paralkar VM, Nandedkar AK, Pointer RH, Kleinman HK, Reddi AH . Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen . The Journal of Biological Chemistry . 265 . 28 . 17281–4 . October 1990 . 10.1016/S0021-9258(17)44900-3 . 2211625 . free .
• Hernandez MR, Igoe F, Neufeld AH . Extracellular matrix of the human optic nerve head . American Journal of Ophthalmology . 102 . 2 . 139–48 . August 1986 . 2426947 . 10.1016/0002-9394(86)90134-0 .
• Aumailley M, Wiedemann H, Mann K, Timpl R . Binding of nidogen and the laminin-nidogen complex to basement membrane collagen type IV . European Journal of Biochemistry . 184 . 1 . 241–8 . September 1989 . 2506015 . 10.1111/j.1432-1033.1989.tb15013.x . free .
• Pihlajaniemi T, Tryggvason K, Myers JC, Kurkinen M, Lebo R, Cheung MC, Prockop DJ, Boyd CD . cDNA clones coding for the pro-alpha1(IV) chain of human type IV procollagen reveal an unusual homology of amino acid sequences in two halves of the carboxyl-terminal domain . The Journal of Biological Chemistry . 260 . 12 . 7681–7 . June 1985 . 10.1016/S0021-9258(17)39662-X . 2581969 . free .
• Brinker JM, Gudas LJ, Loidl HR, Wang SY, Rosenbloom J, Kefalides NA, Myers JC . Restricted homology between human alpha 1 type IV and other procollagen chains . Proceedings of the National Academy of Sciences of the United States of America . 82 . 11 . 3649–53 . June 1985 . 2582422 . 397843 . 10.1073/pnas.82.11.3649 . 1985PNAS...82.3649B . free .
• Soininen R, Huotari M, Ganguly A, Prockop DJ, Tryggvason K . Structural organization of the gene for the alpha 1 chain of human type IV collagen . The Journal of Biological Chemistry . 264 . 23 . 13565–71 . August 1989 . 10.1016/S0021-9258(18)80034-5 . 2701944 . free .
• Siebold B, Deutzmann R, Kühn K . The arrangement of intra- and intermolecular disulfide bonds in the carboxyterminal, non-collagenous aggregation and cross-linking domain of basement-membrane type IV collagen . European Journal of Biochemistry . 176 . 3 . 617–24 . October 1988 . 2844531 . 10.1111/j.1432-1033.1988.tb14321.x .
• Pöschl E, Pollner R, Kühn K . The genes for the alpha 1(IV) and alpha 2(IV) chains of human basement membrane collagen type IV are arranged head-to-head and separated by a bidirectional promoter of unique structure . The EMBO Journal . 7 . 9 . 2687–95 . September 1988 . 10.1002/j.1460-2075.1988.tb03122.x . 2846280 . 457057 .
• Bowcock AM, Hebert JM, Christiano AM, Wijsman E, Cavalli-Sforza LL, Boyd CD . The pro alpha 1 (IV) collagen gene is linked to the D13S3 locus at the distal end of human chromosome 13q . Cytogenetics and Cell Genetics . 45 . 3–4 . 234–6 . 1988 . 2891465 . 10.1159/000132460 .
• Solomon E, Hiorns LR, Spurr N, Kurkinen M, Barlow D, Hogan BL, Dalgleish R . Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family . Proceedings of the National Academy of Sciences of the United States of America . 82 . 10 . 3330–4 . May 1985 . 2987919 . 397769 . 10.1073/pnas.82.10.3330 . 1985PNAS...82.3330S . free .
• Soininen R, Huotari M, Hostikka SL, Prockop DJ, Tryggvason K . The structural genes for alpha 1 and alpha 2 chains of human type IV collagen are divergently encoded on opposite DNA strands and have an overlapping promoter region . The Journal of Biological Chemistry . 263 . 33 . 17217–20 . November 1988 . 10.1016/S0021-9258(19)77818-1 . 3182844 . free .
• Brazel D, Oberbäumer I, Dieringer H, Babel W, Glanville RW, Deutzmann R, Kühn K . Completion of the amino acid sequence of the alpha 1 chain of human basement membrane collagen (type IV) reveals 21 non-triplet interruptions located within the collagenous domain . European Journal of Biochemistry . 168 . 3 . 529–36 . November 1987 . 3311751 . 10.1111/j.1432-1033.1987.tb13450.x .

External links

• GeneReviews/NCBI/NIH/UW entry on COL4A1-Related Disorders - Autosomal Dominant Type 1 Porencephaly; Brain Small Vessel Disease with Hemorrhage; Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps

Notes and References

1. Soininen R, Haka-Risku T, Prockop DJ, Tryggvason K . Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen . FEBS Letters . 225 . 1–2 . 188–94 . December 1987 . 3691802 . 10.1016/0014-5793(87)81155-9 . free .
2. Web site: Entrez Gene: COL4A1 collagen, type IV, alpha 1.
3. Web site: BioGPS - your Gene Portal System. biogps.org. 2016-10-11.
4. Peng. Guicheng. Lin. Maohuan. Zhang. Kun. Chen. Jie. Wang. Yifang. Yang. Yu. Wang. Jingfeng. Huang. Hui. 2013-06-19. Hemoglobin A1c Can Identify More Cardiovascular and Metabolic Risk Profile in OGTT-Negative Chinese Population. International Journal of Medical Sciences. 10. 8. 1028–1034. 10.7150/ijms.5905. 1449-1907. 3691802. 23801890.
5. Web site: COL4A1 - Collagen alpha-1(IV) chain precursor - Homo sapiens (Human) - COL4A1 gene & protein. www.uniprot.org. 2016-10-11.
6. Than. Manuel E.. Henrich. Stefan. Huber. Robert. Ries. Albert. Mann. Karlheinz. Kühn. Klaus. Timpl. Rupert. Bourenkov. Gleb P.. Bartunik. Hans D.. 2002-05-14. The 1.9-A crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type of covalent Met-Lys cross-link. Proceedings of the National Academy of Sciences of the United States of America. 99. 10. 6607–6612. 10.1073/pnas.062183499. 0027-8424. 12011424. 124450. 2002PNAS...99.6607T . free.
7. Peng G, Lin M, Zhang K, Chen J, Wang Y, Yang Y, Wang J, Huang H . Hemoglobin A1c can identify more cardiovascular and metabolic risk profile in OGTT-negative Chinese population . International Journal of Medical Sciences . 10 . 8 . 1028–34 . 2013-06-19 . 23801890 . 3691802 . 10.7150/ijms.5905 .
8. Peissel B, Geng L, Kalluri R, Kashtan C, Rennke HG, Gallo GR, Yoshioka K, Sun MJ, Hudson BG, Neilson EG . Comparative distribution of the alpha 1(IV), alpha 5(IV), and alpha 6(IV) collagen chains in normal human adult and fetal tissues and in kidneys from X-linked Alport syndrome patients . The Journal of Clinical Investigation . 96 . 4 . 1948–57 . October 1995 . 7560087 . 10.1172/JCI118241 . 185832.
9. Maragoudakis ME, Missirlis E, Karakiulakis GD, Sarmonica M, Bastakis M, Tsopanoglou N . Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with anti-tumor properties . Kidney International . 43 . 1 . 147–50 . January 1993 . 7679456 . 10.1038/ki.1993.24. free .
10. Sudhakar A, Nyberg P, Keshamouni VG, Mannam AP, Li J, Sugimoto H, Cosgrove D, Kalluri R . Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin . The Journal of Clinical Investigation . 115 . 10 . 2801–10 . October 2005 . 16151532 . 10.1172/JCI24813 . 1199529.
11. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P . COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps . The New England Journal of Medicine . 357 . 26 . 2687–95 . December 2007 . 18160688 . 10.1056/NEJMoa071906 . free .
12. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, Kakita A, Yamamoto T, Otsuki Y, Shimizu S, Wada T, Koyama N, Mino Y, Kondo N, Takahashi S, Hirabayashi S, Takanashi J, Okumura A, Kumagai T, Hirai S, Nabetani M, Saitoh S, Hattori A, Yamasaki M, Kumakura A, Sugo Y, Nishiyama K, Miyatake S, Tsurusaki Y, Doi H, Miyake N, Matsumoto N, Saitsu H . Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly . Annals of Neurology . 73 . 1 . 48–57 . January 2013 . 23225343 . 10.1002/ana.23736 . 3218598 .
13. Smigiel R, Cabala M, Jakubiak A, Kodera H, Sasiadek MJ, Matsumoto N, Sasiadek MM, Saitsu H . Novel COL4A1 mutation in an infant with severe dysmorphic syndrome with schizencephaly, periventricular calcifications, and cataract resembling congenital infection . en . Birth Defects Research. Part A, Clinical and Molecular Teratology . 106 . 4 . 304–7 . April 2016 . 26879631 . 10.1002/bdra.23488 .
14. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, Li WW, Cui YX, Li XJ, Xue CY . A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family . BMC Medical Genetics . 15 . 97 . 2014-01-01 . 25124159 . 10.1186/s12881-014-0097-2 . 4236509 . free .
15. Turner AW, Nikpay M, Silva A, Lau P, Martinuk A, Linseman TA, Soubeyrand S, McPherson R . Functional interaction between COL4A1/COL4A2 and SMAD3 risk loci for coronary artery disease . Atherosclerosis . 242 . 2 . 543–52 . October 2015 . 26310581 . 10.1016/j.atherosclerosis.2015.08.008 .
16. Yaramis A, Lochmüller H, Töpf A, Sonmezler E, Yilmaz E, Hiz S, Yis U, Gungor S, Ipek Polat A, Edem P, Beltran S, Laurie S, Yaramis A, Horvath R, Oktay Y (2020) COL4A1-related autosomal recessive encephalopathy in 2 Turkish children. Neurol Genet 6(1):e392
17. Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS . Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials . Lancet . 385 . 9984 . 2264–71 . June 2015 . 25748612 . 10.1016/S0140-6736(14)61730-X . 4608367.