Human Genetics

, Volume 96, Issue 1, pp 58–64 | Cite as

Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias

  • J. Bonaventure
  • F. Chaminade
  • P. Maroteaux
Original Investigation


We have used the polymerase chain reaction and single strand conformation polymorphism (SSCP) methods to analyse the COL10A1 gene, which encodes collagen type X, in DNA samples from patients with metaphyseal dysplasia type Schmid (SMCD) and other related forms of metaphyseal dysplasia. Five cases of SMCD were sporadic and three others were familial. Abnormal SSCP profiles were observed in six instances. In two families, the altered pattern segregated with the phenotype. The heterozygous mutations corresponded to a glycine substitution by glutamic acid at position 595 and to an asparagine substitution by lysine at position 617. In one sporadic case, the sequence studies demonstrated that the individual was heterozygous for a single base deletion (del T 1908) that produced a premature stop codon. Three additional mutations were single base substitutions that affected highly conserved residues at positions 597, 644 and 648. In two additional individuals with SMCD, in two patients with unclassifiable forms of metaphyseal dysplasia, and in one family with epiphyso-metaphyseal dysplasia, SSCP analysis detected neutral polymorphisms in the entire coding sequence of the gene but no mutations. Our results demonstrate that mutations in the carboxy-terminal region of collagen X are specific for the SMCD phenotype. Mutations appear to be clustered into three small subdomains: one of them is rich an aromatic residues, the second includes the putative N-linked oligosaccharide attachment site and the third contains mostly hydrophilic residues. The absence of clinical variability between patients carrying heterozygous single base substitutions or small deletions suggests that, in both instances, the mutant collagen chains either fail to be incorporated into stable trimers or disturb type X collagen assembly.


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  1. Apte SS, Olsen BR (1993) Characterization of the mouse type X collagen gene. Matrix 13:165–179Google Scholar
  2. Brass A, Kadler KE, Thomas JT, Grant ME, Boot-Hanford RP (1992) The fibrillar collagens, collagen VIII, collagen X and the C1q complement proteins share a similar domain in their C-terminal non-collagenous regions. FEBS Lett 303:126–128Google Scholar
  3. Chan D, Cole WG, Rogers J, Bateman J (1994) A mutation in the conserved NC1 domain of type X collagen prevents in vitro multimer assembly resulting in a Schmid metaphyseal chondrodysplasia (abstract). Matrix 14:396Google Scholar
  4. Dharmavaram RM, Elberson MA, Peng M, Kirson LA, Kelley TE, Jimenez SA (1994) Identification of a mutation in type X collagen in a family with Schmid metaphyseal chondrodysplasia. Hum Mol Genet 3:507–509Google Scholar
  5. Jacenko O, LuValle PA, Olsen BR (1993) Spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a matrix protein specific for cartilage to bone transition. Nature 365:56–61Google Scholar
  6. Kong RYC, Kwan KM, Lau ET, Thomas JT, Boot-Hanford RP, Grant ME, Cheah KSE (1993) Intron-exon structure, alternative use of the promoter and expression of the mouse collagen X gene, COL10A1. Eur J Biochem 213:99–111Google Scholar
  7. Kwan APL, Cummings CE, Chapman JA, Grant ME (1991) Macromolecular organization of chicken type X collagen in vitro. J Cell Biol 114:597–604Google Scholar
  8. Lachman RS, Rimoin DL, Spranger J (1988) Metaphyseal chondrodysplasia, Schmid type: clinical and radiographic delineation with a review of the literature. Pediatr Radiol 18:93–102Google Scholar
  9. McIntosh I, Abbott MH, Warman ML, Olsen BR, Francomano CA (1994) Additional mutations of type X collagen confirm COL10A1 as the Schmid metaphyseal chondrodysplasia locus. Hum Mol Genet 3:303–307Google Scholar
  10. Rosati R, Horan GS, Pinero GJ, Garofalo S, Keene D, Horton W, Vuorio E, Combrugghe B de, Behringer RR (1994) Normal long bone growth and development in type X collagen null mice. Nature Genet 8:129–135Google Scholar
  11. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NYGoogle Scholar
  12. Schmid TM, Linsenmayer TF (1985) Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol 110:598–605Google Scholar
  13. Spranger J, Winterpacht A, Zabel B (1994) The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr 153:56–65Google Scholar
  14. Sweetman WA, Rash B, Sykes B, Beighton P, Hecht JT, Zabel B, Thomas JT, Boot-Hanford RP, Grant ME, Wallis GA (1992) SSCP and segregation analysis of the human type X collagen gene (COL10A1) in heritable forms of chondrodysplasia. Am J Hum Genet 51:841–849Google Scholar
  15. Thomas JT, Cresswell CJ, Rash B, Nicolai H, Jones T, Solomon E, Grant ME, Boot-Hanford RP (1991a) The human collagen X gene. Complete primary translated sequence and chromosomal localization. Biochem J 280:617–623Google Scholar
  16. Thomas JT, Kwan PL, Grant ME, Boot-Hanford RP (1991b) Isolation of cDNAs encoding the complete sequence of bovine type X collagen. Biochem J 273:141–148Google Scholar
  17. Wallis GA, Rash B, Sweetman WA, Thomas JT, Super M, Evans G, Grant ME, Boot-Hanford RP (1994a) Amino acid substitutions of conserved residues in the carboxyl-terminal domain of the α1 (X) chain of type X collagen occur in two unrelated families with metaphyseal dysplasia type Schmid. Am J Hum Genet 54:169–178Google Scholar
  18. Wallis GA, Rash B, Sykes B, Bonaventure J, Zabel B, Grant ME, Boot-Hanford RP (1994b) Mutations in the gene encoding the alpha1(X) collagen (COL10A1) occur in individuals with metaphyseal chondrodysplasia type Schmid but not in several related forms of chondrodysplasia. Am J Hum Genet 55:A248Google Scholar
  19. Warman ML, Abbott M, Apte SS, Hefferon T, McIntosh I, Cohn DH, Hecht JT, Olsen BR, Francomano CA (1993) A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nature Genet 5:79–82Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • J. Bonaventure
    • 1
  • F. Chaminade
    • 1
  • P. Maroteaux
    • 1
  1. 1.CNRS ER 88. Tour LavoisierHôpital NeckerParis cedex 15France

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