Human Genetics

, Volume 112, Issue 1, pp 84–90

Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia

  • Akihiko Mabuchi
  • Noriyo Manabe
  • Nobuhiko Haga
  • Hiroshi Kitoh
  • Toshiyuki Ikeda
  • Hiroyuki Kawaji
  • Kazuya Tamai
  • Junichiro Hamada
  • Shigeru Nakamura
  • Nicola Brunetti-Pierri
  • Mamori Kimizuka
  • Yoshio Takatori
  • Kozo Nakamura
  • Gen Nishimura
  • Hirofumi Ohashi
  • Shiro Ikegawa
Original Investigation

DOI: 10.1007/s00439-002-0845-9

Cite this article as:
Mabuchi, A., Manabe, N., Haga, N. et al. Hum Genet (2003) 112: 84. doi:10.1007/s00439-002-0845-9

Abstract.

Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs (P=0.0003) and elsewhere in the COMP gene (P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469–473) in the seventh CLR were extremely short (below –6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations (P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.

Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Akihiko Mabuchi
    • 1
  • Noriyo Manabe
    • 2
  • Nobuhiko Haga
    • 2
  • Hiroshi Kitoh
    • 4
  • Toshiyuki Ikeda
    • 1
  • Hiroyuki Kawaji
    • 5
  • Kazuya Tamai
    • 6
  • Junichiro Hamada
    • 6
  • Shigeru Nakamura
    • 7
  • Nicola Brunetti-Pierri
    • 8
  • Mamori Kimizuka
    • 9
  • Yoshio Takatori
    • 2
  • Kozo Nakamura
    • 2
  • Gen Nishimura
    • 3
  • Hirofumi Ohashi
    • 3
  • Shiro Ikegawa
    • 1
  1. 1.Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, c/o Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
  2. 2.Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan
  3. 3.Japanese Skeletal Dysplasia Consortium, Japan
  4. 4.Department of Orthopaedic Surgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan
  5. 5.Department of Orthopaedic Surgery, Sanyudo Hospital, Yonezawa, Yamagata, Japan
  6. 6.Department of Orthopedic Surgery, Dokkyo University School of Medicine, Shimotuga-gun, Saitama, Japan
  7. 7.Department of Orthopaedic Surgery, Teikyo University School of Medicine, Tokyo, Japan
  8. 8.Department of Pediatrics, "Federico II" University, Naples, Italy
  9. 9.Department of Orthopedics, National Rehabilitation Center for Disabled Children, Tokyo, Japan
  10. 10.Division of Medical Genetics, Saitama Children's Medical Center, Iwatsuki, Saitama, Japan