Human Genetics

, Volume 104, Issue 6, pp 492–497

Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)

Authors

  • Isao Nakamura
    • Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan e-mail: yusuke@ims.u-tokyo.ac.jp, Tel.: +81-3-5449-5372, Fax: +81-3-5449-5433
  • Shiro Ikegawa
    • Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan e-mail: yusuke@ims.u-tokyo.ac.jp, Tel.: +81-3-5449-5372, Fax: +81-3-5449-5433
  • Akihiko Okawa
    • Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan e-mail: yusuke@ims.u-tokyo.ac.jp, Tel.: +81-3-5449-5372, Fax: +81-3-5449-5433
  • Shin’ya Okuda
    • Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, and Department of Orthopedic Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
  • Y. Koshizuka
    • Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan e-mail: yusuke@ims.u-tokyo.ac.jp, Tel.: +81-3-5449-5372, Fax: +81-3-5449-5433
  • Hiroshi Kawaguchi
    • Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
  • Kozo Nakamura
    • Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
  • Tsunemaro Koyama
    • Department of Neurosurgery, Ohtsu Municipal Hospital, 2-2-9 Motomiya, Ohtsu-shi, Shiga 520-0804, Japan
  • Sumio Goto
    • Department of Orthopedic Surgery, Chiba University School of Medicine,1-8-1 Inohana, Chyuo-ku, Chiba 260-8670, Japan
  • Junya Toguchida
    • Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
  • Mutsumi Matsushita
    • Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
  • Takahiro Ochi
    • Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, and Department of Orthopedic Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
  • Kunio Takaoka
    • Department of Orthopedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto-shi, Nagano 390-8621, Japan
  • Y. Nakamura
    • Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan e-mail: yusuke@ims.u-tokyo.ac.jp, Tel.: +81-3-5449-5372, Fax: +81-3-5449-5433
Original investigation

DOI: 10.1007/s004390050993

Cite this article as:
Nakamura, I., Ikegawa, S., Okawa, A. et al. Hum Genet (1999) 104: 492. doi:10.1007/s004390050993

Abstract

OPLL (ossification of the posterior longitudinal ligament of the spine) is a common form of human myelopathy with a prevalence of as much as 4% in a variety of ethnic groups. To clarify the genetic factors that predispose to OPLL, we have studied ttw (tiptoe walking), a mouse model that presents ectopic ossification of the spinal ligaments similar to OPLL and have found that the ttw phenotype is caused by the nonsense mutation of the gene encoding nucleotide pyrophosphatase (NPPS), a membrane-bound glycoprotein thought to produce inorganic pyrophosphate, a major inhibitor of calcification and mineralization. To investigate a possible role of NPPS in the etiology of OPLL, we have examined its genetic variations in OPLL patients. A total of 323 OPLL patients was screened by means of polymerase chain reaction/single-strand conformation polymorphism analysis covering all the exons and their surrounding introns, plus about 1.5-kb of the promoter region. We identified ten nucleotide variations in the NPPS gene; five of the alterations caused amino-acid substitutions, and two of them were found specifically in OPLL patients. Subsequently, we performed an association study using these variations and found a significant association of an allele, viz., a deletion of T at a position 11 nucleotides upstream from the splice acceptor site of intron 20 (IVS20–11delT), with OPLL; the proportion of the individuals having this deletion was significantly higher (P = 0.0029) in OPLL patients than in controls, indicating that those who have this variation may be more susceptible to the abnormal ossification of the spinal ligaments. Thus, our study suggests that NPPS plays an important role in the etiology of human OPLL.

Copyright information

© Springer-Verlag Berlin Heidelberg 1999