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Mutations in TRPV4 cause an inherited arthropathy of hands and feet

Nature Genetics volume 43, pages 1142–1146 (2011)Cite this article

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Abstract

Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges1. Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4. Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization. Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress. Others have shown that gain-of-function TRPV4 mutations cause skeletal dysplasias and peripheral neuropathies2,3,4,5,6,7,8,9,10,11. Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis. Our data raise the possibility that TRPV4 may also have a role in age- or injury-related osteoarthritis.

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Figure 1: Pedigree for family 2, and clinical and radiographical features of individuals with FDAB from families 2 and 3.
Figure 2: Schematic diagram of the TRPV4 protein.
Figure 3: Expression of wild-type and mutant TRPV4 in stably transfected HEK-293 cells.
Figure 4: Intracellular calcium levels in stably transfected HEK-293 cells.
Figure 5: TRPV4 expression in mouse growth-plate and articular cartilage.
Figure 6: Trpv4 expression in mice with surgically induced osteoarthritis.

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References

  1. Amor, D.J. et al. Familial digital arthropathy-brachydactyly. Am. J. Med. Genet. 108, 235–240 (2002).

    Article  Google Scholar 

  2. Camacho, N. et al. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am. J. Med. Genet. A. 152A, 1169–1177 (2010).

    Article  CAS  Google Scholar 

  3. Rock, M.J. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat. Genet. 40, 999–1003 (2008).

    Article  CAS  Google Scholar 

  4. Krakow, D. et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am. J. Hum. Genet. 84, 307–315 (2009).

    Article  CAS  Google Scholar 

  5. Deng, H.X. et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat. Genet. 42, 165–169 (2009).

    Article  Google Scholar 

  6. Landoure, G. et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat. Genet. 42, 170–174 (2009).

    Article  Google Scholar 

  7. Nishimura, G. et al. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am. J. Med. Genet. A. 152A, 1443–1449 (2010).

    Article  Google Scholar 

  8. Auer-Grumbach, M. et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat. Genet. 42, 160–164 (2009).

    Article  Google Scholar 

  9. Klein, C.J. et al. TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology 76, 887–894 (2011).

    Article  CAS  Google Scholar 

  10. Chen, D.H. et al. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75, 1968–1975 (2010).

    Article  Google Scholar 

  11. Zimon, M. et al. Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain 133, 1798–1809 (2010).

    Article  Google Scholar 

  12. Cameron, T.L., Belluoccio, D., Farlie, P.G., Brachvogel, B. & Bateman, J.F. Global comparative transcriptome analysis of cartilage formation in vivo. BMC Dev. Biol. 9–20 (2009).

  13. Hellwig, N., Albrecht, N., Harteneck, C., Schultz, G. & Schaefer, M. Homo- and heteromeric assembly of TRPV channel subunits. J. Cell Sci. 118, 917–928 (2005).

    Article  CAS  Google Scholar 

  14. Li, J., Mahajan, A. & Tsai, M.D. Ankyrin repeat: a unique motif mediating protein-protein interactions. Biochemistry 45, 15168–15178 (2006).

    Article  CAS  Google Scholar 

  15. Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G. & Plant, T.D. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat. Cell Biol. 2, 695–702 (2000).

    Article  CAS  Google Scholar 

  16. Watanabe, H. et al. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J. Biol. Chem. 277, 47044–47051 (2002).

    Article  CAS  Google Scholar 

  17. Gao, X., Wu, L. & O'Neil, R.G. Temperature-modulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and -independent pathways. J. Biol. Chem. 278, 27129–27137 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Thorneloe, K.S. et al. N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J. Pharmacol. Exp. Ther. 326, 432–442 (2008).

    Article  CAS  Google Scholar 

  20. Arniges, M., Fernandez-Fernandez, J.M., Albrecht, N., Schaefer, M. & Valverde, M.A. Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J. Biol. Chem. 281, 1580–1586 (2006).

    Article  CAS  Google Scholar 

  21. Dai, J. et al. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J. Med. Genet. 47, 704–709 (2010).

    Article  CAS  Google Scholar 

  22. Andreucci, E. et al. TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families. Orphanet J. Rare Dis. 6, 37 (2011).

    Article  Google Scholar 

  23. Loukin, S., Su, Z. & Kung, C. Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS ONE 6, e19533 (2011).

    Article  CAS  Google Scholar 

  24. Clark, A.L., Votta, B.J., Kumar, S., Liedtke, W. & Guilak, F. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum. 62, 2973–2983 (2010).

    Article  CAS  Google Scholar 

  25. Phan, M.N. et al. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum. 60, 3028–3037 (2009).

    Article  CAS  Google Scholar 

  26. Little, C.B. et al. Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J. Clin. Invest. 117, 1627–1636 (2007).

    Article  CAS  Google Scholar 

  27. Glasson, S.S., Blanchet, T.J. & Morris, E.A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061–1069 (2007).

    Article  CAS  Google Scholar 

  28. Fecto, F. et al. Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. J. Biol. Chem. 286, 17281–17291 (2011).

    Article  CAS  Google Scholar 

  29. Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Little, C.B. et al. ADAMTS-1-knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo. Arthritis Rheum. 52, 1461–1472 (2005).

    Article  CAS  Google Scholar 

  31. Campos-Xavier, A.B. et al. Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia. Am. J. Hum. Genet. 84, 760–770 (2009).

    Article  CAS  Google Scholar 

  32. Zreiqat, H. et al. S100A8 and S100A9 in experimental osteoarthritis. Arthritis Res. Ther. 12, R16 (2010).

    Article  Google Scholar 

  33. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002).

    Article  Google Scholar 

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Acknowledgements

We thank U. Maus for referring one subject to the Institute of Human Genetics in Aachen. This work was supported in part by grants from the National Health and Medical Research Council of Australia (350347, 384414, 436903, 490037, 566834) and by the Victorian Government's Operational Infrastructure Support Program.

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Authors and Affiliations

  1. Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia

    Shireen R Lamandé, Irma L Gresshoff, Lynn Rowley, Daniele Belluoccio, Kumara Kaluarachchi, David J Amor, Ravi Savarirayan & John F Bateman

  2. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    Shireen R Lamandé, Irma L Gresshoff, David J Amor & Ravi Savarirayan

  3. Department of Pharmacology, University of Melbourne, Melbourne, Australia

    Yuan Yuan & Peter McIntyre

  4. Raymond Purves Bone & Joint Research Laboratories, Kolling Institute, University of Sydney, Sydney, Australia

    Christopher B Little

  5. Medical Faculty, Institute of Human Genetics, RWTH Aachen University, Aachen, Germany

    Elke Botzenhart & Klaus Zerres

  6. Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Australia

    David J Amor & Ravi Savarirayan

  7. Division of Pediatric Surgery, University of Alberta, Edmonton, Canada

    William G Cole

  8. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia

    John F Bateman

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  1. Shireen R Lamandé
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Contributions

R.S., D.J.A., E.B., K.Z. and W.G.C. recruited the study participants and collected clinical data. S.R.L., J.F.B., P.M., C.B.L. and R.S. designed and supervised the study. I.L.G. performed the linkage analyses, S.R.L. identified the mutations and made the expression constructs and Y.Y. made the transfected cell lines and carried out the calcium imaging and immunoblotting experiments. L.R. and K.K. performed the quantitative RT-PCR and immunostaining. L.R., D.B. and C.B.L. carried out the mouse osteoarthritis experiments. S.R.L. wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Shireen R Lamandé.

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The authors declare no competing financial interests.

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Lamandé, S., Yuan, Y., Gresshoff, I. et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet 43, 1142–1146 (2011). https://doi.org/10.1038/ng.945

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