5nay

Structural highlights

Disease

[CO4A1_HUMAN] Defects in COL4A1 are a cause of brain small vessel disease with hemorrhage (BSVDH) [MIM:607595]. Brain small vessel diseases underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. Inheritance is autosomal dominant.^{[1] [2] [3] [4] [5]} Defects in COL4A1 are the cause of hereditary angiopathy with nephropathy aneurysms and muscle cramps (HANAC) [MIM:611773]. The clinical renal manifestations include hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy appears to affect both small vessels and large arteries.^{[6] [7]} Defects in COL4A1 are a cause of familial porencephaly (POREN1) [MIM:175780]. Porencephaly is a term used for any cavitation or cerebrospinal fluid-filled cyst in the brain. Porencephaly type 1 is usually unilateral and results from focal destructive lesions such as fetal vascular occlusion or birth trauma. Type 2, or schizencephalic porencephaly, is usually symmetric and represents a primary defect or arrest in the development of the cerebral ventricles.^{[8] [9] [10]}

Function

[CO4A1_HUMAN] Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.^{[11] [12] [13] [14]} Arresten, comprising the C-terminal NC1 domain, inhibits angiogenesis and tumor formation. The C-terminal half is found to possess the anti-angiogenic activity. Specifically inhibits endothelial cell proliferation, migration and tube formation. Inhibits expression of hypoxia-inducible factor 1alpha and ERK1/2 and p38 MAPK activation. Ligand for alpha1/beta1 integrin.^{[15] [16] [17] [18]}

References

1. ↑ Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006 Apr 6;354(14):1489-96. PMID:16598045 doi:10.1056/NEJMoa053727
2. ↑ Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Ann Neurol. 2007 Aug;62(2):177-84. PMID:17696175 doi:10.1002/ana.21191
3. ↑ Vahedi K, Kubis N, Boukobza M, Arnoult M, Massin P, Tournier-Lasserve E, Bousser MG. COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage. Stroke. 2007 May;38(5):1461-4. Epub 2007 Mar 22. PMID:17379824 doi:10.1161/STROKEAHA.106.475194
4. ↑ Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M, Goizet C. Ophthalmological features associated with COL4A1 mutations. Arch Ophthalmol. 2010 Apr;128(4):483-9. doi: 10.1001/archophthalmol.2010.42. PMID:20385946 doi:10.1001/archophthalmol.2010.42
5. ↑ Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, Rizzu P, van der Knaap M, Jardine P. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Eur J Paediatr Neurol. 2010 Mar;14(2):182-7. doi: 10.1016/j.ejpn.2009.04.010., Epub 2009 May 28. PMID:19477666 doi:10.1016/j.ejpn.2009.04.010
6. ↑ 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. N Engl J Med. 2007 Dec 27;357(26):2687-95. PMID:18160688 doi:10.1056/NEJMoa071906
7. ↑ Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Am J Med Genet A. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. PMID:20818663 doi:10.1002/ajmg.a.33659
8. ↑ Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005 May 20;308(5725):1167-71. PMID:15905400 doi:10.1126/science.1109418
9. ↑ Breedveld G, de Coo IF, Lequin MH, Arts WF, Heutink P, Gould DB, John SW, Oostra B, Mancini GM. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet. 2006 Jun;43(6):490-5. Epub 2005 Aug 17. PMID:16107487 doi:10.1136/jmg.2005.035584
10. ↑ de Vries LS, Koopman C, Groenendaal F, Van Schooneveld M, Verheijen FW, Verbeek E, Witkamp TD, van der Worp HB, Mancini G. COL4A1 mutation in two preterm siblings with antenatal onset of parenchymal hemorrhage. Ann Neurol. 2009 Jan;65(1):12-8. doi: 10.1002/ana.21525. PMID:19194877 doi:10.1002/ana.21525
11. ↑ Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R. Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res. 2000 May 1;60(9):2520-6. PMID:10811134
12. ↑ Zheng JP, Tang HY, Chen XJ, Yu BF, Xie J, Wu TC. Construction of recombinant plasmid and prokaryotic expression in E. coli and biological activity analysis of human placenta arresten gene. Hepatobiliary Pancreat Dis Int. 2006 Feb;5(1):74-9. PMID:16481288
13. ↑ 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. J Clin Invest. 2005 Oct;115(10):2801-10. Epub 2005 Sep 8. PMID:16151532 doi:10.1172/JCI24813
14. ↑ Nyberg P, Xie L, Sugimoto H, Colorado P, Sund M, Holthaus K, Sudhakar A, Salo T, Kalluri R. Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor. Exp Cell Res. 2008 Nov 1;314(18):3292-305. doi: 10.1016/j.yexcr.2008.08.011. Epub, 2008 Aug 26. PMID:18775695 doi:10.1016/j.yexcr.2008.08.011
15. ↑ Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R. Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res. 2000 May 1;60(9):2520-6. PMID:10811134
16. ↑ Zheng JP, Tang HY, Chen XJ, Yu BF, Xie J, Wu TC. Construction of recombinant plasmid and prokaryotic expression in E. coli and biological activity analysis of human placenta arresten gene. Hepatobiliary Pancreat Dis Int. 2006 Feb;5(1):74-9. PMID:16481288
17. ↑ 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. J Clin Invest. 2005 Oct;115(10):2801-10. Epub 2005 Sep 8. PMID:16151532 doi:10.1172/JCI24813
18. ↑ Nyberg P, Xie L, Sugimoto H, Colorado P, Sund M, Holthaus K, Sudhakar A, Salo T, Kalluri R. Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor. Exp Cell Res. 2008 Nov 1;314(18):3292-305. doi: 10.1016/j.yexcr.2008.08.011. Epub, 2008 Aug 26. PMID:18775695 doi:10.1016/j.yexcr.2008.08.011