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Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

Nature Genetics volume 40, pages 999–1003 (2008)Cite this article

Abstract

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature1. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1–12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4α-phorbol 12,13-didecanoate (4αPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.

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Figure 1: Pedigree and haplotypes for family R99-102.
Figure 2: Radiographs of the proband at age 8 years, 3 months.
Figure 3: Gene expression analysis throughout the linked region of chromosome 12.
Figure 4: Expression of human TRPV4 and the R616Q mutant in HEK293 cells.
Figure 5: Expression of TRPV4 in HEK 293 cells.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (HD22657) and the Human Frontiers Science Program (HFSP Research Grant Ref. RGP 32/2004), the Belgian Federal Government, the Flemish Government, the Onderzoeksraad KU Leuven (GOA 2004/07, F.W.O. G.0136.00; F.W.O. G.0172.03, Interuniversity Poles of Attraction Program, Prime Ministers Office IUAP Nr.3P4/23, Excellentiefinanciering EF/95/010) to B.N. Microarray data were generated and analyses were performed within the University of California, Los Angeles DNA microarray facility. We thank the families for their active participation.

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Authors and Affiliations

  1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Matthew J Rock, Vincent A Funari, Tara L Funari, Ralph S Lachman, William R Wilcox, David L Rimoin & Daniel H Cohn

  2. Department of Molecular Cell Biology, Katholieke Universiteit (KU) Leuven, Laboratory for Ion Channel Research, Campus Gasthuisberg, Leuven, B-3000, Belgium

    Jean Prenen, Grzegorz Owsianik, Annelies Janssens, Thomas Voets & Bernd Nilius

  3. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Barry Merriman, Stanley F Nelson, David L Rimoin & Daniel H Cohn

  4. Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Stanley F Nelson, Ralph S Lachman, William R Wilcox, David L Rimoin & Daniel H Cohn

  5. Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Ralph S Lachman

  6. Servicio de Traumatología y Ortopedia, Hospital Pereira Rossel, Montevideo, Uruguay

    Soraya Reyno

  7. Instituto de Genética Médica, Hospital Italiano, Montevideo, Uruguay

    Roberto Quadrelli & Alicia Vaglio

  8. Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, Tokyo, Japan

    Shiro Ikegawa

  9. Department of Pediatrics, Koshigaya Hospital, Dokkyo University, Saitama, Japan

    Toshiro Nagai

  10. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    David L Rimoin

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  1. Matthew J Rock
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  2. Jean Prenen
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Contributions

M.J.R., J.P., T.V., B.N., S.F.N. and D.H.C. designed the experiments. M.J.R., J.P., G.O., A.J., B.M. and V.A.F. carried out the experiments. T.L.F., R.S.L., W.R.W., S.R., R.Q., A.V., S.I., T.N. and D.L.R. ascertained and diagnosed the subjects. M.J.R., B.N. and D.H.C. wrote the manuscript.

Corresponding author

Correspondence to Daniel H Cohn.

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Rock, M., Prenen, J., Funari, V. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40, 999–1003 (2008). https://doi.org/10.1038/ng.166

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