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Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family
  1. J Dai1,2,
  2. O-H Kim3,
  3. T-J Cho4,
  4. M Schmidt-Rimpler5,
  5. H Tonoki6,
  6. K Takikawa7,
  7. N Haga7,8,
  8. K Miyoshi7,9,
  9. H Kitoh10,
  10. W-J Yoo4,
  11. I-H Choi4,
  12. H-R Song11,
  13. D-K Jin12,
  14. H-T Kim13,
  15. H Kamasaki14,
  16. P Bianchi15,
  17. G Grigelioniene16,
  18. S Nampoothiri17,
  19. M Minagawa18,
  20. S-i Miyagawa19,
  21. T Fukao20,
  22. C Marcelis21,
  23. M C E Jansweijer22,
  24. R C M Hennekam23,
  25. F Bedeschi24,
  26. A Mustonen25,
  27. Q Jiang2,
  28. H Ohashi26,
  29. T Furuichi1,
  30. S Unger5,
  31. B Zabel5,
  32. E Lausch5,
  33. A Superti-Furga5,
  34. G Nishimura27,
  35. S Ikegawa1
  1. 1Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, Tokyo, Japan
  2. 2The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
  3. 3Department of Radiology, Ajou University Hospital, Suwon, Korea
  4. 4Department of Orthopaedic Surgery, Seoul National University Children's Hospital, Seoul, Korea
  5. 5Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  6. 6Department of Pediatrics and Medical Genetics Section, Tenshi Hospital, Sapporo, Japan
  7. 7Department of Paediatric Orthopedics, Shizuoka Children's Hospital, Shizuoka, Japan
  8. 8Department of Rehabilitation Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  9. 9Department of Spine Surgery, Yokohama Rosai Hospital, Yokohama, Japan
  10. 10Department of Orthopaedic Surgery, Nagoya University School of Medicine, Nagoya, Japan
  11. 11Department of Orthopaedic Surgery, Korea University Guro Hospital, Seoul, Korea
  12. 12Department of Pediatrics, Samsung Medical Center, Seoul, Korea
  13. 13Department of Orthopaedic Surgery, Pusan National University Hospital, Pusan, Korea
  14. 14Department of Pediatrics, School of Medicine, Sapporo Medical University, Sapporo, Japan
  15. 15Neonatal Intensive Care Unit, Ospedali Riuniti, Bergamo, Italy
  16. 16Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden
  17. 17Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, AIMS Ponekkara PO, Cochin, Kerala, India
  18. 18Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
  19. 19Department of Pediatrics, National Hospital Organization, Kure Medical Center, Kure, Japan
  20. 20Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
  21. 21Department of Clinical Genetics, 849 Antropogenetica, Radboud University Medical Centre, Nijmegen, The Netherlands
  22. 22Department of Pediatric Genetics, Emma Childrens' Hospital/Academic Medical Center, Amsterdam, The Netherlands
  23. 23Department of Pediatrics, Academic Medical Center, University of Amsterdam, AZ Amsterdam, The Netherlands
  24. 24Clinical Genetic Unit, Department of Obstetrics and Pediatrics, Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milano, Italy
  25. 25Department of Clinical Genetics, Oulu University Hospital, Oulu, Oys, Finland
  26. 26Division of Medical Genetics, Saitama Children's Medical Center, Iwatsuki, Japan
  27. 27Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Kiyose, Japan
  1. Correspondence to Shiro Ikegawa, Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan; sikegawa{at}


Background Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear.

Objectives and methods To examine TRPV4 mutation spectrum and phenotype−genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.

Results TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations.

Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showed genotype−phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

  • Diagnosis
  • calcium and bone
  • genetics
  • molecular genetics
  • connective tissue disease

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  • Funding Grants-in-aids from the Ministry of Education, Culture, Sports and Science of Japan; Research on Child Health and Development; Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea; European Skeletal Dysplasia Network (ESDN;; Japanese Skeletal Dysplasia Consortium (JSDC;; German Ministry for Education and Research (BMBF contract grant “SKELNET”); European Union (FP6, Contract grant “EuroGrow”); University of Freiburg; Deutsche Forschungsgemeinschaft.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Ethical Committee of RIKEN, Japan.

  • Provenance and peer review Not commissioned; externally peer reviewed.