3fby

Structural highlights

Disease

COMP_HUMAN Defects in COMP are the cause of multiple epiphyseal dysplasia type 1 (EDM1) [MIM:132400. EDM is a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. EDM is broadly categorized into the more severe Fairbank and the milder Ribbing types.^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} Defects in COMP are the cause of pseudoachondroplasia (PSACH) [MIM:177170. PSAC is a dominantly inherited chondrodysplasia characterized by short stature and early-onset osteoarthrosis. PSACH is more severe than EDM1 and is recognized in early childhood.^{[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]}

Function

COMP_HUMAN May play a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors. Could play a role in the pathogenesis of osteoarthritis. Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses apoptosis by blocking the activation of caspase-3 and by inducing the IAP family of survival proteins (BIRC3, BIRC2, BIRC5 and XIAP). Essential for maintaining a vascular smooth muscle cells (VSMCs) contractile/differentiated phenotype under physiological and pathological stimuli. Maintains this phenotype of VSMCs by interacting with ITGA7 (By similarity).^{[22] [23] [24]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P. Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. J Biol Chem. 2001 Mar 2;276(9):6083-92. Epub 2000 Nov 17. PMID:11084047 doi:10.1074/jbc.M009512200
2. ↑ Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES, et al.. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet. 1995 Jul;10(3):330-6. PMID:7670472 doi:http://dx.doi.org/10.1038/ng0795-330
3. ↑ Ballo R, Briggs MD, Cohn DH, Knowlton RG, Beighton PH, Ramesar RS. Multiple epiphyseal dysplasia, ribbing type: a novel point mutation in the COMP gene in a South African family. Am J Med Genet. 1997 Feb 11;68(4):396-400. PMID:9021009
4. ↑ Susic S, McGrory J, Ahier J, Cole WG. Multiple epiphyseal dysplasia and pseudoachondroplasia due to novel mutations in the calmodulin-like repeats of cartilage oligomeric matrix protein. Clin Genet. 1997 Apr;51(4):219-24. PMID:9184241
5. ↑ Briggs MD, Mortier GR, Cole WG, King LM, Golik SS, Bonaventure J, Nuytinck L, De Paepe A, Leroy JG, Biesecker L, Lipson M, Wilcox WR, Lachman RS, Rimoin DL, Knowlton RG, Cohn DH. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet. 1998 Feb;62(2):311-9. PMID:9463320 doi:10.1086/301713
6. ↑ Ikegawa S, Ohashi H, Nishimura G, Kim KC, Sannohe A, Kimizuka M, Fukushima Y, Nagai T, Nakamura Y. Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet. 1998 Dec;103(6):633-8. PMID:9921895
7. ↑ Loughlin J, Irven C, Mustafa Z, Briggs MD, Carr A, Lynch SA, Knowlton RG, Cohn DH, Sykes B. Identification of five novel mutations in cartilage oligomeric matrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mutat. 1998;Suppl 1:S10-7. PMID:9452026
8. ↑ Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perala M, Carter L, Spector TD, Kolodziej L, Seppanen U, Glazar R, Krolewski J, Latos-Bielenska A, Ala-Kokko L. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. 2001 Nov;69(5):969-80. Epub 2001 Sep 14. PMID:11565064 doi:10.1086/324023
9. ↑ Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. 2012 Jan;33(1):144-57. doi: 10.1002/humu.21611. Epub 2011 Oct 31. PMID:21922596 doi:10.1002/humu.21611
10. ↑ Chen H, Deere M, Hecht JT, Lawler J. Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. J Biol Chem. 2000 Aug 25;275(34):26538-44. PMID:10852928 doi:10.1074/jbc.M909780199
11. ↑ Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P. Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. J Biol Chem. 2001 Mar 2;276(9):6083-92. Epub 2000 Nov 17. PMID:11084047 doi:10.1074/jbc.M009512200
12. ↑ Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES, et al.. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet. 1995 Jul;10(3):330-6. PMID:7670472 doi:http://dx.doi.org/10.1038/ng0795-330
13. ↑ Susic S, McGrory J, Ahier J, Cole WG. Multiple epiphyseal dysplasia and pseudoachondroplasia due to novel mutations in the calmodulin-like repeats of cartilage oligomeric matrix protein. Clin Genet. 1997 Apr;51(4):219-24. PMID:9184241
14. ↑ Briggs MD, Mortier GR, Cole WG, King LM, Golik SS, Bonaventure J, Nuytinck L, De Paepe A, Leroy JG, Biesecker L, Lipson M, Wilcox WR, Lachman RS, Rimoin DL, Knowlton RG, Cohn DH. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet. 1998 Feb;62(2):311-9. PMID:9463320 doi:10.1086/301713
15. ↑ Ikegawa S, Ohashi H, Nishimura G, Kim KC, Sannohe A, Kimizuka M, Fukushima Y, Nagai T, Nakamura Y. Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet. 1998 Dec;103(6):633-8. PMID:9921895
16. ↑ Loughlin J, Irven C, Mustafa Z, Briggs MD, Carr A, Lynch SA, Knowlton RG, Cohn DH, Sykes B. Identification of five novel mutations in cartilage oligomeric matrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mutat. 1998;Suppl 1:S10-7. PMID:9452026
17. ↑ Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. 2012 Jan;33(1):144-57. doi: 10.1002/humu.21611. Epub 2011 Oct 31. PMID:21922596 doi:10.1002/humu.21611
18. ↑ Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M, et al.. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet. 1995 Jul;10(3):325-9. PMID:7670471 doi:http://dx.doi.org/10.1038/ng0795-325
19. ↑ Susic S, Ahier J, Cole WG. Pseudoachondroplasia due to the substitution of the highly conserved Asp482 by Gly in the seventh calmodulin-like repeat of cartilage oligomeric matrix protein. Hum Mutat. 1998;Suppl 1:S125-7. PMID:9452063
20. ↑ Unger S, Korkko J, Krakow D, Lachman RS, Rimoin DL, Cohn DH. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet. 2001 Nov 22;104(2):140-6. PMID:11746045
21. ↑ Mabuchi A, Haga N, Ikeda T, Manabe N, Ohashi H, Takatori Y, Nakamura K, Ikegawa S. Novel mutation in exon 18 of the cartilage oligomeric matrix protein gene causes a severe pseudoachondroplasia. Am J Med Genet. 2001 Nov 22;104(2):135-9. PMID:11746044
22. ↑ Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J. Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J Biol Chem. 2005 Sep 23;280(38):32655-61. Epub 2005 Jul 28. PMID:16051604 doi:10.1074/jbc.M504778200
23. ↑ Koelling S, Clauditz TS, Kaste M, Miosge N. Cartilage oligomeric matrix protein is involved in human limb development and in the pathogenesis of osteoarthritis. Arthritis Res Ther. 2006;8(3):R56. Epub 2006 Mar 15. PMID:16542502 doi:10.1186/ar1922
24. ↑ Gagarina V, Carlberg AL, Pereira-Mouries L, Hall DJ. Cartilage oligomeric matrix protein protects cells against death by elevating members of the IAP family of survival proteins. J Biol Chem. 2008 Jan 4;283(1):648-59. Epub 2007 Nov 8. PMID:17993464 doi:10.1074/jbc.M704035200
25. ↑ Tan K, Duquette M, Joachimiak A, Lawler J. The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding. FASEB J. 2009 Aug;23(8):2490-501. Epub 2009 Mar 10. PMID:19276170 doi:10.1096/fj.08-128090