Abstract
Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca2+ influx was substantially reduced even after stimulation with 4αPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Fleury, P. & Hageman, G. A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J. Neurol. Neurosurg. Psychiatry 48, 1037–1048 (1985).
Isozumi, K. et al. Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum. Mol. Genet. 5, 1377–1382 (1996).
van der Vleuten, A.J. et al. Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23-q24. Eur. J. Hum. Genet. 6, 376–382 (1998).
McEntagart, M.E. et al. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann. Neurol. 57, 293–297 (2005); erratum 57, 609 (2005).
Rock, M.J. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat. Genet. 40, 999–1003 (2008).
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).
Masuyama, R. et al. TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab. 8, 257–265 (2008).
Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003).
Liedtke, W. & Friedman, J.M. Abnormal osmotic regulation in trpv4−/− mice. Proc. Natl. Acad. Sci. USA 100, 13698–13703 (2003).
Pedersen, S.F., Owsianik, G. & Nilius, B. TRP channels: an overview. Cell Calcium 38, 233–252 (2005).
Clapham, D.E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).
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).
Liedtke, W., Tobin, D.M., Bargmann, C.I. & Friedman, J.M. Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 100 Suppl 2, 14531–14536 (2003).
Nilius, B., Watanabe, H. & Vriens, J. The TRPV4 channel: structure-function relationship and promiscuous gating behaviour. Pflugers Arch. 446, 298–303 (2003).
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).
Nilius, B., Owsianik, G., Voets, T. & Peters, J.A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).
Liedtke, W. Molecular mechanisms of TRPV4-mediated neural signaling. Ann. NY Acad. Sci. 1144, 42–52 (2008).
Watanabe, H., Murakami, M., Ohba, T., Takahashi, Y. & Ito, H. TRP channel and cardiovascular disease. Pharmacol. Ther. 118, 337–351 (2008).
Erler, I., Hirnet, D., Wissenbach, U., Flockerzi, V. & Niemeyer, B.A. Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. J. Biol. Chem. 279, 34456–34463 (2004).
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).
Arniges, M., Fernández-Fernández, 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).
Cuajungco, M.P. et al. PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4. J. Biol. Chem. 281, 18753–18762 (2006).
McCleverty, C.J., Koesema, E., Patapoutian, A., Lesley, S.A. & Kreusch, A. Crystal structure of the human TRPV2 channel ankyrin repeat domain. Protein Sci. 15, 2201–2206 (2006).
Lishko, P.V., Procko, E., Jin, X., Phelps, C.B. & Gaudet, R. The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54, 905–918 (2007).
Phelps, C.B., Huang, R.J., Lishko, P.V., Wang, R.R. & Gaudet, R. Structural analyses of the ankyrin repeat domain of TRPV6 and related TRPV ion channels. Biochemistry 47, 2476–2484 (2008).
Erler, I. et al. Trafficking and assembly of the cold-sensitive TRPM8 channel. J. Biol. Chem. 281, 38396–38404 (2006).
Zerangue, N., Schwappach, B., Jan, N.Y. & Jan, L.Y. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron 22, 537–548 (1999).
Nilius, B., Owsianik, G. & Voets, T. Transient receptor potential channels meet phosphoinositides. EMBO J. 27, 2809–2816 (2008).
van Rossum, D.B. et al. Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434, 99–104 (2005).
Weissmann, N. et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc. Natl. Acad. Sci. USA 103, 19093–19098 (2006).
Acknowledgements
We are grateful to the subjects and their families who participated in this study. This work was supported by the Austrian Science Fund (FWF, P19455-B05), the Oesterreichische Nationalbank (ÖNB, project 13010) and by the Interdisciplinary Centre for Clinical Research BIOMAT within the Faculty of Medicine, RWTH Aachen. J.S. is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft (DFG). We thank M. Absenger, M. Hatz, A. Hof, H. Knausz, M. Schabhüttl, A. Gungl and T. Kueznik for expert technical assistance.
Author information
Authors and Affiliations
Contributions
M.A.-G., S.U., J.S., M.E.M., A.H.C., K.J.D., C.M.A.v.R.-A., N.E.A., H.L., B.S.-W., R.P., C.L., G.W.P., H.J.S., H.K. and T.R.P. recruited the study participants, acquired clinical data, conducted neurological and neurophysiological evaluations and performed linkage analysis. M.A.-G, C.G., L.P. and C.F. carried out the Affymetrix array linkage studies and identified the mutations. A.O., Z.B. and B.T. designed, carried out and analyzed the electrophysiological and Ca2+-imaging studies. E.F. conducted immunofluorescence and immunohistochemistry studies. H.S. conducted fluorescence-activated cell sorting (FACS) and biotinylation studies. A.K. performed structural biology and biocomputing analyses. A.H.C., M.E.M. and H.K. participated in the data analysis and reviewed the manuscript. M.A.-G. and C.G. analyzed the data, designed and supervised the study and wrote the manuscript.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7, Supplementary Tables 1–5 and Supplementary Note (PDF 2302 kb)
Rights and permissions
About this article
Cite this article
Auer-Grumbach, M., Olschewski, A., Papić, L. et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42, 160–164 (2010). https://doi.org/10.1038/ng.508
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.508