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


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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  1. Shohat, M., Lachman, R., Gruber, H.E. & Rimoin, D.L. Brachyolmia: radiographic and genetic evidence of heterogeneity. Am. J. Med. Genet. 33, 209–219 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Kornak, U. & Mundlos, S. Genetic disorders of the skeleton: a developmental approach. Am. J. Hum. Genet. 73, 447–474 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Superti-Furga, A., Bonafe, L. & Rimoin, D.L. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am. J. Med. Genet. 106, 282–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Horton, W.A., Langer, L.O., Collins, D.L. & Dwyer, C. Brachyolmia, recessive type (Hobaek): a clinical, radiographic, and histochemical study. Am. J. Med. Genet. 16, 201–211 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Toledo, S.P.A. et al. Recessively inherited, late onset spondylar dysplasia and peripheral corneal opacity with anomalies in urinary mucopolysaccharides: a possible error of chondroitin-6-sulfate synthesis. Am. J. Med. Genet. 2, 385–395 (1978).

    Article  CAS  PubMed  Google Scholar 

  6. Fontaine, G., Maroteaux, P., Farriaux, J.P. & Bosquet, M. Pure spondyloepiphyseal dysplasia or brachyolmia. Arch. Fr. Pediatr. 32, 493 (1975).

    CAS  PubMed  Google Scholar 

  7. Gardner, J. & Beighton, P. Brachyolmia: an autosomal dominant form. Am. J. Med. Genet. 49, 308–312 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Funari, V.A. et al. Cartilage-selective genes identified in genome-scale analysis of non-cartilage and cartilage gene expression. BMC Genomics 8, 165–177 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Liedtke, W. et al. Vanilloid receptor–related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nilius, B., Watanabe, H. & Vriens, J. The TRPV4 channel: structure-function relationship and promiscuous gating behaviour. Pflugers Arch. 446, 298–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Nilius, B., Owsianik, G., Voets, T. & Peters, J.A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Pedersen, S.F., Owsianik, G. & Nilius, B. TRP channels: an overview. Cell Calcium 38, 233–252 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Nilius, B., Vriens, J., Prenen, J., Droogmans, G. & Voets, T. TRPV4 calcium entry channel: a paradigm for gating diversity. Am. J. Physiol. Cell Physiol. 286, C195–C205 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Watanabe, H. et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424, 434–438 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Watanabe, H. et al. Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J. Biol. Chem. 277, 13569–13577 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. D'hoedt, D. et al. Stimulus-specific modulation of the cation channel TRPV4 by PACSIN 3. J. Biol. Chem. 283, 6272–6280 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Vriens, J., Owsianik, G., Janssens, A., Voets, T. & Nilius, B. Determinants of 4 alpha-phorbol sensitivity in transmembrane domains 3 and 4 of the cation channel TRPV4. J. Biol. Chem. 282, 12796–12803 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Watanabe, H. et al. Modulation of TRPV4 gating by intra- and extracellular Ca2+. Cell Calcium 33, 489–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, Y. et al. OS-9 regulates the transit and polyubiquitination of TRPV4 in the endoplasmic reticulum. J. Biol. Chem. 282, 36561–36570 (2007); published online 11 October 2007.

    Article  CAS  PubMed  Google Scholar 

  20. Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Muramatsu, S. et al. Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J. Biol. Chem. 282, 32158–32167 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Foster, J.W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372, 525–530 (1994).

    Article  CAS  Google Scholar 

  23. Chikuda, H. et al. Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Genes Dev. 18, 2418–2429 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Becker, D., Blasé, C., Bereiter-Hahn, J. & Jendrach, M. TRPV4 exhibits a functional role in cell-volume regulation. J. Cell Sci. 118, 2435–2440 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Hunziker, E.B. Mechanism of longitudinal bone growth and its regulation by growth plate chondrocytes. Microsc. Res. Tech. 28, 505–519 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Olsen, B.R. et al. Genetic and epigenetic determinants of skeletal morphogenesis – role of cellular polarity and ciliary function in skeletal development and growth. Oral Biosci. Med. 2, 57–65 (2005).

    Google Scholar 

  27. Xiao, Z. et al. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J. Biol. Chem. 281, 30884–30895 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Giamarchi, A. et al. The versatile nature of the calcium-permeable cation channel TRPP2. EMBO Rep. 7, 787–793 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lange, K. et al. Mendel version 4.0: a complete package for the exact genetic analysis of discrete traits in pedigree and population data sets. Am. J. Hum. Genet. 69 (Suppl.), A1886 (2001).

    Google Scholar 

  30. Nilius, B., Prenen, J., Wissenbach, U., Bodding, M. & Droogmans, G. Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells. Pflügers Archiv. Eur. J. Phys. 443, 227–233 (2001).

    Article  CAS  Google Scholar 

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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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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.

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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).

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