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. 2000 Apr;37(4):263–271. doi: 10.1136/jmg.37.4.263

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder

G Mortier 1, M Weis 1, L Nuytinck 1, L King 1, D Wilkin 1, A De Paepe 1, R Lachman 1, D Rimoin 1, D Eyre 1, D Cohn 1
PMCID: PMC1734564  PMID: 10745044

Abstract

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal α1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proα1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.


Keywords: type II collagen disorders; achondrogenesis II-hypochondrogenesis; spondyloepiphyseal dysplasia congenita; COL2A1

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Selected References

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  1. Bogaert R., Tiller G. E., Weis M. A., Gruber H. E., Rimoin D. L., Cohn D. H., Eyre D. R. An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis. J Biol Chem. 1992 Nov 5;267(31):22522–22526. [PubMed] [Google Scholar]
  2. Bogaert R., Wilkin D., Wilcox W. R., Lachman R., Rimoin D., Cohn D. H., Eyre D. R. 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):1128–1136. [PMC free article] [PubMed] [Google Scholar]
  3. Bonaventure J., Cohen-Solal L., Ritvaniemi P., Van Maldergem L., Kadhom N., Delezoide A. L., Maroteaux P., Prockop D. J., Ala-Kokko L. Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis: analysis of genotype-phenotype relationships. Biochem J. 1995 May 1;307(Pt 3):823–830. doi: 10.1042/bj3070823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borochowitz Z., Ornoy A., Lachman R., Rimoin D. L. Achondrogenesis II-hypochondrogenesis: variability versus heterogeneity. Am J Med Genet. 1986 Jun;24(2):273–288. doi: 10.1002/ajmg.1320240208. [DOI] [PubMed] [Google Scholar]
  5. Chan D., Cole W. G., Chow C. W., Mundlos S., Bateman J. F. 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):1747–1753. [PubMed] [Google Scholar]
  6. Chan D., Cole W. G. Low basal transcription of genes for tissue-specific collagens by fibroblasts and lymphoblastoid cells. Application to the characterization of a glycine 997 to serine substitution in alpha 1(II) collagen chains of a patient with spondyloepiphyseal dysplasia. J Biol Chem. 1991 Jul 5;266(19):12487–12494. [PubMed] [Google Scholar]
  7. Chan D., Rogers J. F., Bateman J. F., Cole W. G. Recurrent substitutions of arginine 789 by cysteine in pro-alpha 1 (II) collagen chains produce spondyloepiphyseal dysplasia congenita. J Rheumatol Suppl. 1995 Feb;43:37–38. [PubMed] [Google Scholar]
  8. Chan D., Taylor T. K., Cole W. G. 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):15238–15245. [PubMed] [Google Scholar]
  9. Cole W. G., Hall R. K., Rogers J. G. 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. doi: 10.1136/jmg.30.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fernandes R. J., Wilkin D. J., Weis M. A., Wilcox W. R., Cohn D. H., Rimoin D. L., Eyre D. R. Incorporation of structurally defective type II collagen into cartilage matrix in kniest chondrodysplasia. Arch Biochem Biophys. 1998 Jul 15;355(2):282–290. doi: 10.1006/abbi.1998.0745. [DOI] [PubMed] [Google Scholar]
  11. Freisinger P., Ala-Kokko L., LeGuellec D., Franc S., Bouvier R., Ritvaniemi P., Prockop D. J., Bonaventure J. Mutation in the COL2A1 gene in a patient with hypochondrogenesis. Expression of mutated COL2A1 gene is accompanied by expression of genes for type I procollagen in chondrocytes. J Biol Chem. 1994 May 6;269(18):13663–13669. [PubMed] [Google Scholar]
  12. Freisinger P., Bonaventure J., Stoess H., Pontz B. F., Emmrich P., Nerlich A. Type II collagenopathies: are there additional family members? Am J Med Genet. 1996 May 3;63(1):137–143. doi: 10.1002/(SICI)1096-8628(19960503)63:1<137::AID-AJMG24>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  13. Godfrey M., Hollister D. W. Type II achondrogenesis-hypochondrogenesis: identification of abnormal type II collagen. Am J Hum Genet. 1988 Dec;43(6):904–913. [PMC free article] [PubMed] [Google Scholar]
  14. Godfrey M., Keene D. R., Blank E., Hori H., Sakai L. Y., Sherwin L. A., Hollister D. W. Type II achondrogenesis-hypochondrogenesis: morphologic and immunohistopathologic studies. Am J Hum Genet. 1988 Dec;43(6):894–903. [PMC free article] [PubMed] [Google Scholar]
  15. Horton W. A., Machado M. A., Ellard J., Campbell D., Bartley J., Ramirez F., Vitale E., Lee B. Characterization of a type II collagen gene (COL2A1) mutation identified in cultured chondrocytes from human hypochondrogenesis. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4583–4587. doi: 10.1073/pnas.89.10.4583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kuivaniemi H., Tromp G., Prockop D. J. 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. 1997;9(4):300–315. doi: 10.1002/(SICI)1098-1004(1997)9:4<300::AID-HUMU2>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  17. 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):978–980. doi: 10.1126/science.2543071. [DOI] [PubMed] [Google Scholar]
  18. Maroteaux P., Stanescu V., Stanescu R. Hypochondrogenesis. Eur J Pediatr. 1983 Oct;141(1):14–22. doi: 10.1007/BF00445662. [DOI] [PubMed] [Google Scholar]
  19. Mortier G. R., Wilkin D. J., Wilcox W. R., Rimoin D. L., Lachman R. S., Eyre D. R., Cohn D. H. 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):285–288. doi: 10.1093/hmg/4.2.285. [DOI] [PubMed] [Google Scholar]
  20. Mundlos S., Chan D., McGill J., Bateman J. F. An alpha 1(II) Gly913 to Cys substitution prevents the matrix incorporation of type II collagen which is replaced with type I and III collagens in cartilage from a patient with hypochondrogenesis. Am J Med Genet. 1996 May 3;63(1):129–136. doi: 10.1002/(SICI)1096-8628(19960503)63:1<129::AID-AJMG23>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  21. Spranger J. Pattern recognition in bone dysplasias. Prog Clin Biol Res. 1985;200:315–342. [PubMed] [Google Scholar]
  22. Spranger J., Winterpacht A., Zabel B. The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr. 1994 Feb;153(2):56–65. doi: 10.1007/BF01959208. [DOI] [PubMed] [Google Scholar]
  23. Tiller G. E., Polumbo P. A., Weis M. A., Bogaert R., Lachman R. S., Cohn D. H., Rimoin D. L., Eyre D. R. Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type. Nat Genet. 1995 Sep;11(1):87–89. doi: 10.1038/ng0995-87. [DOI] [PubMed] [Google Scholar]
  24. Tiller G. E., Rimoin D. L., Murray L. W., Cohn D. H. 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):3889–3893. doi: 10.1073/pnas.87.10.3889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tiller G. E., Weis M. A., Polumbo P. A., Gruber H. E., Rimoin D. L., Cohn D. H., Eyre D. R. An RNA-splicing mutation (G+5IVS20) in the type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenita. Am J Hum Genet. 1995 Feb;56(2):388–395. [PMC free article] [PubMed] [Google Scholar]
  26. Vikkula M., Ritvaniemi P., Vuorio A. F., Kaitila I., Ala-Kokko L., Peltonen L. A mutation in the amino-terminal end of the triple helix of type II collagen causing severe osteochondrodysplasia. Genomics. 1993 Apr;16(1):282–285. doi: 10.1006/geno.1993.1179. [DOI] [PubMed] [Google Scholar]
  27. Vissing H., D'Alessio M., Lee B., Ramirez F., Godfrey M., Hollister D. W. 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):18265–18267. [PubMed] [Google Scholar]
  28. Weis M. A., Wilkin D. J., Kim H. J., Wilcox W. R., Lachman R. S., Rimoin D. L., Cohn D. H., Eyre D. R. Structurally abnormal type II collagen in a severe form of Kniest dysplasia caused by an exon 24 skipping mutation. J Biol Chem. 1998 Feb 20;273(8):4761–4768. doi: 10.1074/jbc.273.8.4761. [DOI] [PubMed] [Google Scholar]
  29. Winterpacht A., Hilbert M., Schwarze U., Mundlos S., Spranger J., Zabel B. U. Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet. 1993 Apr;3(4):323–326. doi: 10.1038/ng0493-323. [DOI] [PubMed] [Google Scholar]
  30. Zabel B., Hilbert K., Stöss H., Superti-Furga A., Spranger J., Winterpacht A. A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia. Am J Med Genet. 1996 May 3;63(1):123–128. doi: 10.1002/(SICI)1096-8628(19960503)63:1<123::AID-AJMG22>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]

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