6hg7

Structural highlights

Disease

[CO2A1_HUMAN] Defects in COL2A1 are the cause of spondyloepiphyseal dysplasia congenital type (SEDC) [MIM:183900]. This disorder is characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems.^{[1] [2] [3] [4] [5] [6] [7] [8]} Defects in COL2A1 are the cause of spondyloepimetaphyseal dysplasia, Strudwick type (SEMDSTWK) [MIM:184250]. A bone disease characterized by disproportionate short stature from birth, with a very short trunk and shortened limbs, and skeletal abnormalities including lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses. A distinctive radiographic feature is irregular sclerotic changes, described as dappled in the metaphyses of the long bones.[:]^{[9] [10]} Defects in COL2A1 are the cause of achondrogenesis type 2 (ACG2) [MIM:200610]; also known as achondrogenesis-hypochondrogenesis type II. ACG2 is a disease characterized by the absence of ossification in the vertebral column, sacrum and pubic bones.^{[11] [12] [13] [14] [15] [16] [17]} Defects in COL2A1 are the cause of Legg-Calve-Perthes disease (LCPD) [MIM:150600]; also known as Legg-Perthes disease or Perthes disease. LCPD is characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone.^[18] Defects in COL2A1 are the cause of Kniest dysplasia (KD) [MIM:156550]; also known as Kniest syndrome or metatropic dwarfism type II. KD is a moderately severe chondrodysplasia phenotype that results from mutations in the COL2A1 gene. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss.^{[19] [20]} Defects in COL2A1 are a cause of primary avascular necrosis of femoral head (ANFH) [MIM:608805]; also known as ischemic necrosis of the femoral head or osteonecrosis of the femoral head. ANFH causes disability that often requires surgical intervention. Most cases are sporadic, but families in which there is an autosomal dominant inheritance of the disease have been identified. It has been estimated that 300,000 to 600,000 people in the United States have ANFH. Approximately 15,000 new cases of this common and disabling disorder are reported annually. The age at the onset is earlier than that for osteoarthritis. The diagnosis is typically made when patients are between the ages of 30 and 60 years. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. Moreover, nearly 10 percent of the 500,000 total-hip arthroplasties performed each year in the United States involve patients with ANFH. As a result, this disease creates a substantial socioeconomic cost as well as a burden for patients and their families.^[21] Defects in COL2A1 are the cause of osteoarthritis with mild chondrodysplasia (OACD) [MIM:604864]. Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage. Some forms of osteoarthritis are secondary to events such as trauma, infections, metabolic disorders, or congenital or heritable conditions that deform the epiphyses or related structures. In most patients, however, there is no readily identifiable cause of osteoarthritis. Inheritance in a Mendelian dominant manner has been demonstrated in some families with primary generalized osteoarthritis. Reports demonstrate coinheritance of primary generalized osteoarthritis with specific alleles of the gene COL2A1, the precursor of the major protein of cartilage.^{[22] [23] [24] [25]} Defects in COL2A1 are the cause of platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T) [MIM:151210]. Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-T is characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondro-osseous junction. PLSD-T is generally a perinatally lethal disease, but a few long-term survivors have been reported.^{[26] [27] [28]} Defects in COL2A1 are the cause of multiple epiphyseal dysplasia with myopia and conductive deafness (EDMMD) [MIM:132450]. Multiple epiphyseal dysplasia 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. EDMMD is an autosomal dominant disorder characterized by epiphyseal dysplasia associated with progressive myopia, retinal thinning, crenated cataracts, conductive deafness.^[29] Defects in COL2A1 are the cause of spondyloperipheral dysplasia (SPD) [MIM:271700]. SPD patients manifest short stature, midface hypoplasia, sensorineural hearing loss, spondyloepiphyseal dysplasia, platyspondyly and brachydactyly. Defects in COL2A1 are the cause of Stickler syndrome type 1 (STL1) [MIM:108300]; also known as vitreous type 1, or membranous vitreous type. STL1 is an autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable.^{[30] [31] [32] [33] [34] [35]} Defects in COL2A1 are the cause of Stickler syndrome type 1 non-syndromic ocular (STL1O) [MIM:609508]. STL1O is an autosomal dominant form of Stickler syndrome characterized by the ocular signs typically seen in STL1 such as cataract, myopia, retinal detachment. STL1 systemic features of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities are either absent or very mild in STL1O patients. Defects in COL2A1 are a cause of rhegmatogenous retinal detachment autosomal dominant (DRRD) [MIM:609508]. Rhegmatogenous retinal detachment most frequently results from a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina. It is often associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated.^{[36] [37]} Defects in COL2A1 are the cause of Czech dysplasia (CZECHD) [MIM:609162]. A skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes.^{[38] [39] [40] [41]}

Function

[CO2A1_HUMAN] Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces.

References

1. ↑ Lee B, Vissing H, Ramirez F, Rogers D, Rimoin D. Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science. 1989 May 26;244(4907):978-80. PMID:2543071
2. ↑ Tiller GE, Rimoin DL, Murray LW, Cohn DH. Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia. Proc Natl Acad Sci U S A. 1990 May;87(10):3889-93. PMID:2339128
3. ↑ Chan D, Taylor TK, Cole WG. Characterization of an arginine 789 to cysteine substitution in alpha 1 (II) collagen chains of a patient with spondyloepiphyseal dysplasia. J Biol Chem. 1993 Jul 15;268(20):15238-45. PMID:8325895
4. ↑ Cole WG, Hall RK, Rogers JG. The clinical features of spondyloepiphyseal dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1(II) chain of type II collagen. J Med Genet. 1993 Jan;30(1):27-35. PMID:8423604
5. ↑ Ritvaniemi P, Sokolov BP, Williams CJ, Considine E, Yurgenev L, Meerson EM, Ala-Kokko L, Prockop DJ. A single base mutation in the type II procollagen gene (COL2A1) that converts glycine alpha 1-247 to serine in a family with late-onset spondyloepiphyseal dysplasia. Hum Mutat. 1994;3(3):261-7. PMID:8019561 doi:http://dx.doi.org/10.1002/humu.1380030314
6. ↑ Williams CJ, Rock M, Considine E, McCarron S, Gow P, Ladda R, McLain D, Michels VM, Murphy W, Prockop DJ, et al.. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519-->Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet. 1995 Feb;4(2):309-12. PMID:7757086
7. ↑ Sobetzko D, Eich G, Kalff-Suske M, Grzeschik KH, Superti-Furga A. Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual. Am J Med Genet. 2000 Jan 31;90(3):239-42. PMID:10678662
8. ↑ 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
9. ↑ Tiller GE, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR. Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type. Nat Genet. 1995 Sep;11(1):87-9. PMID:7550321 doi:http://dx.doi.org/10.1038/ng0995-87
10. ↑ Sulko J, Czarny-Ratajczak M, Wozniak A, Latos-Bielenska A, Kozlowski K. Novel amino acid substitution in the Y-position of collagen type II causes spondyloepimetaphyseal dysplasia congenita. Am J Med Genet A. 2005 Sep 1;137A(3):292-7. PMID:16088915 doi:10.1002/ajmg.a.30881
11. ↑ Williams CJ, Rock M, Considine E, McCarron S, Gow P, Ladda R, McLain D, Michels VM, Murphy W, Prockop DJ, et al.. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519-->Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet. 1995 Feb;4(2):309-12. PMID:7757086
12. ↑ Vissing H, D'Alessio M, Lee B, Ramirez F, Godfrey M, Hollister DW. Glycine to serine substitution in the triple helical domain of pro-alpha 1 (II) collagen results in a lethal perinatal form of short-limbed dwarfism. J Biol Chem. 1989 Nov 5;264(31):18265-7. PMID:2572591
13. ↑ Mortier GR, Wilkin DJ, Wilcox WR, Rimoin DL, Lachman RS, Eyre DR, Cohn DH. A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691-->Arg) in the type II collagen trimer. Hum Mol Genet. 1995 Feb;4(2):285-8. PMID:7757081
14. ↑ Chan D, Cole WG, Chow CW, Mundlos S, Bateman JF. A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage. J Biol Chem. 1995 Jan 27;270(4):1747-53. PMID:7829510
15. ↑ Korkko J, Cohn DH, Ala-Kokko L, Krakow D, Prockop DJ. Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. Am J Med Genet. 2000 May 15;92(2):95-100. PMID:10797431
16. ↑ Mortier GR, Weis M, Nuytinck L, King LM, Wilkin DJ, De Paepe A, Lachman RS, Rimoin DL, Eyre DR, Cohn DH. Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder. J Med Genet. 2000 Apr;37(4):263-71. PMID:10745044
17. ↑ Forzano F, Lituania M, Viassolo A, Superti-Furga V, Wildhardt G, Zabel B, Faravelli F. A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and "patchy" expression in the mosaic father. Am J Med Genet A. 2007 Dec 1;143A(23):2815-20. PMID:17994563 doi:10.1002/ajmg.a.32047
18. ↑ Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, Ikegawa S. A recurrent mutation in type II collagen gene causes Legg-Calve-Perthes disease in a Japanese family. Hum Genet. 2007 Jun;121(5):625-9. Epub 2007 Mar 30. PMID:17394019 doi:10.1007/s00439-007-0354-y
19. ↑ Wilkin DJ, Bogaert R, Lachman RS, Rimoin DL, Eyre DR, Cohn DH. A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia. Hum Mol Genet. 1994 Nov;3(11):1999-2003. PMID:7874117
20. ↑ Winterpacht A, Superti-Furga A, Schwarze U, Stoss H, Steinmann B, Spranger J, Zabel B. The deletion of six amino acids at the C-terminus of the alpha 1 (II) chain causes overmodification of type II and type XI collagen: further evidence for the association between small deletions in COL2A1 and Kniest dysplasia. J Med Genet. 1996 Aug;33(8):649-54. PMID:8863156
21. ↑ Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, Su JS, Huang SF, Hsiao KJ, Fann CS, Hwang HW, Chen YT, Tsai SF. Type II collagen gene variants and inherited osteonecrosis of the femoral head. N Engl J Med. 2005 Jun 2;352(22):2294-301. PMID:15930420 doi:352/22/2294
22. ↑ Williams CJ, Rock M, Considine E, McCarron S, Gow P, Ladda R, McLain D, Michels VM, Murphy W, Prockop DJ, et al.. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519-->Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet. 1995 Feb;4(2):309-12. PMID:7757086
23. ↑ Ala-Kokko L, Baldwin CT, Moskowitz RW, Prockop DJ. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6565-8. PMID:1975693
24. ↑ Eyre DR, Weis MA, Moskowitz RW. Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia. J Clin Invest. 1991 Jan;87(1):357-61. PMID:1985108 doi:http://dx.doi.org/10.1172/JCI114994
25. ↑ Holderbaum D, Malemud CJ, Moskowitz RW, Haqqi TM. Human cartilage from late stage familial osteoarthritis transcribes type II collagen mRNA encoding a cysteine in position 519. Biochem Biophys Res Commun. 1993 May 14;192(3):1169-74. PMID:8507190 doi:http://dx.doi.org/S0006-291X(83)71539-1
26. ↑ Mortier GR, Weis M, Nuytinck L, King LM, Wilkin DJ, De Paepe A, Lachman RS, Rimoin DL, Eyre DR, Cohn DH. Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder. J Med Genet. 2000 Apr;37(4):263-71. PMID:10745044
27. ↑ Nishimura G, Nakashima E, Mabuchi A, Shimamoto K, Shimamoto T, Shimao Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S. Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type. J Med Genet. 2004 Jan;41(1):75-9. PMID:14729840
28. ↑ Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, Omran H, Wright M, Hilbert K, Bonafe L, Spranger J, Zabel B, Superti-Furga A. Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies. Am J Med Genet A. 2005 Feb 15;133A(1):61-7. PMID:15643621 doi:10.1002/ajmg.a.30531
29. ↑ Ballo R, Beighton PH, Ramesar RS. Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene. Am J Med Genet. 1998 Oct 30;80(1):6-11. PMID:9800905
30. ↑ Korkko J, Ritvaniemi P, Haataja L, Kaariainen H, Kivirikko KI, Prockop DJ, Ala-Kokko L. Mutation in type II procollagen (COL2A1) that substitutes aspartate for glycine alpha 1-67 and that causes cataracts and retinal detachment: evidence for molecular heterogeneity in the Wagner syndrome and the Stickler syndrome (arthro-ophthalmopathy) Am J Hum Genet. 1993 Jul;53(1):55-61. PMID:8317498
31. ↑ Bogaert R, Wilkin D, Wilcox WR, Lachman R, Rimoin D, Cohn DH, Eyre DR. Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia. Am J Hum Genet. 1994 Dec;55(6):1128-36. PMID:7977371
32. ↑ Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, Scott JD, Snead MP. Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am J Hum Genet. 2000 Nov;67(5):1083-94. Epub 2000 Sep 25. PMID:11007540 doi:S0002-9297(07)62938-3
33. ↑ Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. PMID:16752401 doi:10.1002/humu.20347
34. ↑ McAlinden A, Majava M, Bishop PN, Perveen R, Black GC, Pierpont ME, Ala-Kokko L, Mannikko M. Missense and nonsense mutations in the alternatively-spliced exon 2 of COL2A1 cause the ocular variant of Stickler syndrome. Hum Mutat. 2008 Jan;29(1):83-90. PMID:17721977 doi:10.1002/humu.20603
35. ↑ Richards AJ, McNinch A, Martin H, Oakhill K, Rai H, Waller S, Treacy B, Whittaker J, Meredith S, Poulson A, Snead MP. Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1. Hum Mutat. 2010 Jun;31(6):E1461-71. doi: 10.1002/humu.21257. PMID:20513134 doi:10.1002/humu.21257
36. ↑ Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, Scott JD, Snead MP. Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am J Hum Genet. 2000 Nov;67(5):1083-94. Epub 2000 Sep 25. PMID:11007540 doi:S0002-9297(07)62938-3
37. ↑ Richards AJ, Meredith S, Poulson A, Bearcroft P, Crossland G, Baguley DM, Scott JD, Snead MP. A novel mutation of COL2A1 resulting in dominantly inherited rhegmatogenous retinal detachment. Invest Ophthalmol Vis Sci. 2005 Feb;46(2):663-8. PMID:15671297 doi:10.1167/iovs.04-1017
38. ↑ Williams CJ, Rock M, Considine E, McCarron S, Gow P, Ladda R, McLain D, Michels VM, Murphy W, Prockop DJ, et al.. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519-->Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet. 1995 Feb;4(2):309-12. PMID:7757086
39. ↑ Williams CJ, Considine EL, Knowlton RG, Reginato A, Neumann G, Harrison D, Buxton P, Jimenez S, Prockop DJ. Spondyloepiphyseal dysplasia and precocious osteoarthritis in a family with an Arg75-->Cys mutation in the procollagen type II gene (COL2A1). Hum Genet. 1993 Nov;92(5):499-505. PMID:8244341
40. ↑ Tzschach A, Tinschert S, Kaminsky E, Lusga E, Mundlos S, Graul-Neumann LM. Czech dysplasia: report of a large family and further delineation of the phenotype. Am J Med Genet A. 2008 Jul 15;146A(14):1859-64. doi: 10.1002/ajmg.a.32389. PMID:18553548 doi:10.1002/ajmg.a.32389
41. ↑ Matsui Y, Michigami T, Tachikawa K, Yamazaki M, Kawabata H, Nishimura G. Czech dysplasia occurring in a Japanese family. Am J Med Genet A. 2009 Oct;149A(10):2285-9. doi: 10.1002/ajmg.a.33010. PMID:19764028 doi:10.1002/ajmg.a.33010
42. ↑ Gebauer JM, Kohler A, Dietmar H, Gompert M, Neundorf I, Zaucke F, Koch M, Baumann U. COMP and TSP-4 interact specifically with the novel GXKGHR motif only found in fibrillar collagens. Sci Rep. 2018 Nov 21;8(1):17187. doi: 10.1038/s41598-018-35447-8. PMID:30464261 doi:http://dx.doi.org/10.1038/s41598-018-35447-8