Skip to main content
SpringerLink
Log in

Hereditary Channelopathies Caused by TRPV4 Mutations

  • Chapter
  • First Online:
Book cover Pathologies of Calcium Channels

Abstract

Mutations in the transient receptor potential vanilloid 4 gene (TRPV4), encoding a widely expressed Ca2+-permeable ion channel, result in autosomal dominant diseases of peripheral nerve (Charcot-Marie-Tooth disease type 2C, congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy) or the skeletal system (metatropic dysplasia, spondylometaphyseal dysplasia Kozlowski type, spondyloepiphyseal dysplasia Maroteaux type, autosomal dominant brachyolmia, parastremmatic dysplasia, familial digital arthropathy-brachydactyly). TRPV4-mediated nerve and bone disorders are characterised by considerable phenotypic variability, including severe congenital-onset disease to complete nonpenetrance in the case of nerve disease-associated mutations. Most often, individual TRPV4 mutations have been associated with distinct organ system diseases; although overlap syndromes may occur. Heterologous expression studies have identified a number of functional changes in the TRPV4 ion channel resulting from disease-causing mutations, the most prominent being increased constitutive channel activity. As many of these changes are shared by TRPV4 mutants causing different diseases, however, it remains unclear how particular mutations in TRPV4 result in such diverse disease phenotypes. In this chapter, we outline the clinical and pathological features of the known forms of TRPV4-mediated disease, as well as the effects of disease-causing mutations on TRPV4 assembly, expression and channel activity. We also explore current thinking on the pathogenenic mechanisms contributing to different forms of TRPV4 channelopathy. Elucidation of these mechanisms will be an important step in the development of new therapeutic interventions for these diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adams C, Suchowersky O, Lowry RB (1998) Congenital autosomal dominant distal spinal muscular atrophy. Neuromuscul Disord 8:405–408

    PubMed  CAS  Google Scholar 

  • Aharoni S, Harlalka G, Offiah A, Shuper A, Crosby AH, McEntagart M (2011) Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder. Am J Med Genet Part A 155:3153–3156

    Google Scholar 

  • Akiyama H (2008) Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol 18:213–219

    PubMed  CAS  Google Scholar 

  • Alessandri-Haber N, Dina OA, Chen X, Levine JD (2009) TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci 29(19):6217–6228

    PubMed  CAS  Google Scholar 

  • Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24(18):4444–4452

    PubMed  CAS  Google Scholar 

  • Almeida-Souza L, Asselbergh B, d’Ydewalle C, Moonens K, Goethals S, de Winter V, Azmi A, Irobi J, Timmermans JP, Gevaert K, Remaut H, Van Den Bosch L, Timmerman V, Janssens S (2011) Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. J Neurosci 31(43):15320–15328

    PubMed  CAS  Google Scholar 

  • Amor DJ, Tudball C, Gardner RJ, Lamandé SR, Bateman JF, Savarirayan R (2002) Familial digital arthropathy-brachydactyly. Am J Med Genet 108:235–240

    PubMed  Google Scholar 

  • Andreucci E, Aftimos S, Alcausin M, Haan E, Hunter W, Kannu P, Kerr B, McGillivray G, McKinlay Gardner RJ, Patricelli MG, Sillence D, Thompson E, Zacharin M, Zankl A, Lamande SR, Savarirayan R (2011) TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families. Orphanet J Rare Dis 6:37

    PubMed  Google Scholar 

  • Arniges M, Fernandez-Fernandez JM, Albrecht N, Schaefer M, Valverde MA (2006) Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J Biol Chem 281(3):1580–1586

    PubMed  CAS  Google Scholar 

  • Astrea G, Brisca G, Fiorillo C, Valle M, Tosetti M, Bruno C, Santorelli FM, Battini R (2012) Muscle MRI in TRPV4-related congenital distal SMA. Neurology 78:364–365

    PubMed  CAS  Google Scholar 

  • Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Fröhlich E, Bálint Z, Tang B, Strohmaier H, Lochmüller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CM, Pieber TR, Crosby AH, Guelly C (2010) Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42(2):160–164

    PubMed  CAS  Google Scholar 

  • Becker D, Muller M, Leuner K, Jendrach M (2008) The C-terminal domain of TRPV4 is essential for plasma membrane localization. Mol Membr Biol 25(2):139–151

    PubMed  CAS  Google Scholar 

  • Berciano J, Baets J, Gallardo E, Zimoń M, Garcia A, López-Laso E, Combarros O, Infante J, Timmerman V, Jordanova A, De Jonghe P (2011) Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation. J Neurol 258:1413–1421

    PubMed  Google Scholar 

  • Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, Nilius B, Boyce BF, Cohn DH (2010) Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet Part A 152(5):1169–1177

    Google Scholar 

  • Cameron TL, Belluoccio D, Farlie PG, Brachvogel B, Bateman JF (2007) Global transcriptome analysis of cartilage formation in vivo. BMC Dev Biol 9:20

    Google Scholar 

  • Chen DH, Sul Y, Weiss M, Hillel A, Lipe H, Wolff J, Matsushita M, Raskind W, Bird T (2010) CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75(22):1968–1975

    PubMed  Google Scholar 

  • Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, Chae JH, Yoo WJ, Tanaka Y, Matsui Y, Takigami I, Monges S, Zabel B, Shimizu K, Nishimura G, Lausch E, Ikegawa S (2012) TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients. Am J Med Genet Part A 158:795–802

    CAS  Google Scholar 

  • Chung MK, Lee H, Caterina MJ (2003) Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J Biol Chem 278:32037–32046

    PubMed  CAS  Google Scholar 

  • Clark AL, Votta BJ, Kumar S, Liedtke W, Guilak F (2010) 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

    PubMed  CAS  Google Scholar 

  • Clark K, Middelbeek J, van Leeuwen FN (2008) Interplay between TRP channels and the cytoskeleton in health and disease. Eur J Cell Biol 87:631–640

    PubMed  CAS  Google Scholar 

  • Cuajungco MP, Grimm C, Oshima K, D’Hoedt D, Nilius B, Mensenkamp AR, Bindels RJ, Plomann M, Heller S (2006) PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4. J Biol Chem 281(27):18753–18762

    PubMed  CAS  Google Scholar 

  • D’Hoedt D, Owsianik G, Prenen J, Cuajungco MP, Grimm C, Heller S, Voets T, Nilius B (2008) Stimulus-specific modulation of the cation channel TRPV4 by PACSIN 3. J Biol Chem 283(10):6272–6280

    PubMed  Google Scholar 

  • D’Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, Vanden Berghe P, Timmerman V, Robberecht W, Van Den Bosch L (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med 17(8):968–974

    PubMed  Google Scholar 

  • Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, Haga N, Miyoshi K, Kitoh H, Yoo WJ, Choi IH, Song HR, Jin DK, Kim HT, Kamasaki H, Bianchi P, Grigelioniene G, Nampoothiri S, Minagawa M, Miyagawa SI, Fukao T, Marcelis C, Jansweijer MC, Hennekam RC, Bedeschi F, Mustonen A, Jiang Q, Ohashi H, Furuichi T, Unger S, Zabel B, Lausch E, Superti-Furga A, Nishimura G, Ikegawa S (2010) Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet 47(10):704–709

    PubMed  CAS  Google Scholar 

  • De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, Di Marzo V (2012) Cannabinoid actions at TRPV4 channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol 204:255–266

    Google Scholar 

  • DeLong R, Siddique T (1992) A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features. Arch Neurol 49:905–908

    PubMed  CAS  Google Scholar 

  • Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau HJ, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, Delong R, Martina M, Dyck PJ, Siddique T (2010) Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 42 (2):165-169

    PubMed  CAS  Google Scholar 

  • Donaghy M, Kennett R (1999) Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy. J Neurol 246:552–555

    PubMed  CAS  Google Scholar 

  • Du J, Wong WY, Sun L, Huang Y, Yao X (2012) Protein kinase G inhibits flow-induced Ca2+ entry into collecting duct cells. J Am Soc Nephrol 23:1172–1180

    Google Scholar 

  • Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, Aronson AE (1994) Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol 35:608–615

    PubMed  CAS  Google Scholar 

  • Everaerts W, Nilius B, Owsianik G (2010a) The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog Biophys Mol Biol 103(1):2–17

    PubMed  CAS  Google Scholar 

  • Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, Hayward NJ, McNamara CR, Xue F, Moran MM, Strassmaier T, Uykal E, Owsianik G, Vennekens R, De Ridder D, Nilius B, Fanger CM, Voets T (2010b) Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Nat Acad Sci USA 107(44):19084–19089

    Google Scholar 

  • Facer P, Casula MA, Smith GD, Benham CD, Chessell IP, Bountra C, Sinisi M, Birch R, Anand P (2007) Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol 7:11

    PubMed  Google Scholar 

  • Fan HC, Zhang X, McNaughton PA (2009) Activation of the TRPV4 ion channel is enhanced by phosphorylation. J Biol Chem 284:27884-27891

    CAS  Google Scholar 

  • Fawcett KA, Murphy SM, Polke JM, Wray S, Burchell VS, Marji H, Quinlivan RM, Zdebik AA, Reilly MM, Houlden H (2012) Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls. J Neurol Neurosurg Psychiatry 83:1204–1209

    PubMed  Google Scholar 

  • Fecto F, Shi Y, Huda R, Martina M, Siddique T, Deng HX (2011) Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. J Biol Chem 286(19):17281–17291

    PubMed  CAS  Google Scholar 

  • Fernandez–Fernandez JM, Andrade YN, Arniges M, Fernandes J, Plata C, Rubio-Moscardo F, Vazquez E, Valverde MA (2008) Functional coupling of TRPV4 cationic channel and large conductance, calcium-dependent potassium channel in human bronchial epithelial cell lines. Pflügers Arch 457(1):149–159

    PubMed  Google Scholar 

  • Fiorillo C, Moro F, Brisca G, Astrea G, Nesti C, Balint Z, Olschewski A, Meschini MC, Guelly C, Auer-Grumbach M, Battini R, Pedemonte M, Romano A, Menchise V, Biancheri R, Santorelli FM, Bruno C (2012) TRPV4 mutations in children with congenital distal spinal muscular atrophy. Neurogenetics 13:195–203

    PubMed  CAS  Google Scholar 

  • Fiorio Pla A, Ong HL, Cheng KT, Brossa A, Bussolati B, Lockwich T, Paria B, Munaron L, Ambudkar IS (2012) TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling. Oncogene 31(2):200–212

    PubMed  CAS  Google Scholar 

  • Fleury P, Hageman G (1985) A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J Neurol Neurosurg Psychiatry 48:1037–1048

    PubMed  CAS  Google Scholar 

  • Gao X, Wu L, O’Neil RG (2003) 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(29):27129–27137

    PubMed  CAS  Google Scholar 

  • Garcia-Elias A, Lorenzo IM, Vicente R, Valverde MA (2008) IP3 receptor binds to and sensitizes TRPV4 channel to osmotic stimuli via a calmodulin-binding site. J Biol Chem 283:31284–31288

    PubMed  CAS  Google Scholar 

  • Gaudet R (2008) A primer on ankyrin repeat function in TRP channels and beyond. Mol BioSyst 4(5):372–379

    PubMed  CAS  Google Scholar 

  • Geneviève D, Le Merrer M, Feingold J, Munnich A, Maroteaux P, Cormier-Daire V (2008) Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature. Am J Med Genet Part A 146:992–996

    Google Scholar 

  • Gevaert T, Vriens J, Segal A, Everaerts W, Roskams T, Talavera K, Owsianik G, Liedtke W, Daelemans D, Dewachter I, Van Leuven F, Voets T, De Ridder D, Nilius B (2007) Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 117(11):3453–3462

    PubMed  CAS  Google Scholar 

  • Goswami C, Kuhn J, Heppenstall PA, Hucho T (2010) Importance of non-selective cation channel TRPV4 interaction with cytoskeleton and their reciprocal regulations in cultured cells. PLoS ONE 5(7):e11654

    PubMed  Google Scholar 

  • Grosskreutz J, Van Den Bosch L, Keller BU (2010) Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium 47:165–174

    PubMed  CAS  Google Scholar 

  • Güler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414

    PubMed  Google Scholar 

  • Hdud IM, El-Shafei AA, Loughna P, Barrett-Jolley R, Mobasheri A (2012) Expression of transient receptor potential vanilloid (TRPV) channels in different passages of articular chondrocytes. Int J Mol Sci 13:4433–4445

    PubMed  CAS  Google Scholar 

  • Hellwig N, Albrecht N, Harteneck C, Schultz G, Schaefer M (2005) Homo- and heteromeric assembly of TRPV channel subunits. J Cell Sci 118(Pt 5):917–928

    PubMed  CAS  Google Scholar 

  • Inada H, Procko E, Sotomayor M, Gaudet R (2012) Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. Biochemistry 51:6195–6206

    PubMed  CAS  Google Scholar 

  • Isozumi K, DeLong R, Kaplan J, Deng HX, Iqbal Z, Hung WY, Wilhelmsen KC, Hentati A, Pericak-Vance MA, Siddique T (1996) Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum Mol Genet 5:1377–1382

    PubMed  CAS  Google Scholar 

  • Jang Y, Jung J, Kim H, Oh J, Jeon JH, Jung S, Kim KT, Cho H, Yang DJ, Kim SM, Kim IB, Song MR, Oh U (2012) Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth. J Biol Chem 287(8):6014–6024

    PubMed  CAS  Google Scholar 

  • Jin M, Wu Z, Chen L, Jaimes J, Collins D, Walters ET, O’Neil RG (2011) Determinants of TRPV4 activity following selective activation by small molecule agonist GSK1016790A. PLoS ONE 6:e16713

    PubMed  CAS  Google Scholar 

  • Kannu P, Aftimos S, Mayne V, Donnan L, Savarirayan R (2007) Metatropic dysplasia: clinical and radiographic findings in 11 patients demonstrating long-term natural history. Am J Med Genet Part A 143:2512–2522

    Google Scholar 

  • Kida N, Sokabe T, Kashio M, Haruna K, Mizuno Y, Suga Y, Nishikawa K, Kanamaru A, Hongo M, Oba A, Tominaga M (2012) Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes. Pflügers Arch 463:715–725

    PubMed  CAS  Google Scholar 

  • Klausen TK, Pagani A, Minassi A, Ech-Chahad A, Prenen J, Owsianik G, Hoffmann EK, Pedersen SF, Appendino G, Nilius B (2009) Modulation of the transient receptor potential vanilloid channel TRPV4 by 4α-phorbol esters: a structure-activity study. J Med Chem 52:2933–2939

    PubMed  CAS  Google Scholar 

  • Klein CJ, Cunningham JM, Atkinson EJ, Schaid DJ, Hebbring SJ, Anderson SA, Klein DM, Dyck PJ, Litchy WJ, Thibodeau SN, Dyck PJ (2003) The gene for HMSN2C maps to 12q23–24: a region of neuromuscular disorders. Neurology 60:1151–1156

    PubMed  CAS  Google Scholar 

  • Klein CJ, Shi Y, Fecto F, Donaghy M, Nicholson G, McEntagart ME, Crosby AH, Wu Y, Lou H, McEvoy KM, Siddique T, Deng HX, Dyck PJ (2011) TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology 76(10):887–894

    PubMed  CAS  Google Scholar 

  • Köttgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer-Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G (2008) TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182:437–447

    Google Scholar 

  • Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH (2009) Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet 84(3):307–315

    PubMed  CAS  Google Scholar 

  • Lamandé SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, Little CB, Botzenhart E, Zerres K, Amor DJ, Cole WG, Savarirayan R, McIntyre P, Bateman JF (2011) Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet 43(11):1142–1146

    PubMed  Google Scholar 

  • Lanciotti A, Brignone MS, Molinari P, Visentin S, De Nuccio C, Macchia G, Aiello C, Bertini E, Aloisi F, Petrucci TC, Ambrosini E (2012) Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations. Hum Mol Genet 21(10):2166–2180

    PubMed  CAS  Google Scholar 

  • Landouré G, Sullivan JM, Johnson JO, Munns CH, Shi Y, Diallo O, Gibbs JR, Gaudet R, Ludlow CL, Fischbeck KH, Traynor BJ, Burnett BG, Sumner CJ (2012) Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology 79:192–194

    PubMed  Google Scholar 

  • Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ (2010) Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 42(2):170–174

    PubMed  Google Scholar 

  • Langer LO, Petersen D, Spranger J (1970) An unusual bone dysplasia: parastremmatic dwarfism. Am J Roentgenol Radium Ther Nucl Med 110:550–560

    PubMed  CAS  Google Scholar 

  • Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm S, May M, Pischke S, Suzuki M, Ibañez-Tallon I, Luft FC, Jordan J, Lewin GR (2011) The molecular and cellular identity of peripheral osmoreceptors. Neuron 69(2):332–344

    PubMed  CAS  Google Scholar 

  • Lev S, Katz B, Minke B (2012) The activity of the TRP-like channel depends on its expression system. Channels 6:86–93

    PubMed  CAS  Google Scholar 

  • Li J, Kanju P, Patterson M, Chew WL, Cho SH, Gilmour I, Oliver T, Yasuda R, Ghio A, Simon SA, Liedtke W (2011) TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles. Environ Health Perspect 119(6):784–793

    PubMed  CAS  Google Scholar 

  • Liedtke W (2008) Molecular mechanisms of TRPV4-mediated neural signaling. Ann NY Acad Sci 1144:42–52

    PubMed  CAS  Google Scholar 

  • Liedtke W, Guilak F (2010) Transient receptor potential vanilloid 4: the sixth sense of the musculoskeletal system? Ann N Y Acad Sci 1192:404–409

    PubMed  Google Scholar 

  • Long F, Ornitz DM (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5(1):a008334

    PubMed  Google Scholar 

  • Loukin S, Su Z, Kung C (2011) Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS ONE 6(5):e19533

    PubMed  CAS  Google Scholar 

  • Loukin S, Su Z, Zhou X, Kung C (2010a) Forward genetic analysis reveals multiple gating mechanisms of TRPV4. J Biol Chem 285(26):19884–19890

    PubMed  CAS  Google Scholar 

  • Loukin S, Zhou X, Su Z, Saimi Y, Kung C (2010b) Wild-type and brachyolmia-causing mutant TRPV4 channels respond directly to stretch force. J Biol Chem 285:27176–27181

    PubMed  CAS  Google Scholar 

  • Ma X, Cao J, Luo J, Nilius B, Huang Y, Ambukar IS, Yao X (2010) Depletion of intracellular Ca2+ store stimulates the translocation of vanilloid transient receptor potential 4-C1 heteromeric channels to the plasma membrane. Arterioscler Thromb Vasc Biol 30:2249–2255

    Google Scholar 

  • Ma X, Cheng KT, Wong CO, O'Neil RG, Birnbaumer L, Ambudkar IS, Yao X (2011a) Heteromeric TRPV4-C1 channels contribute to store-operated Ca(2+) entry in vascular endothelial cells. Cell Calcium 50:502–509

    Google Scholar 

  • Ma X, Nilius B, Wong JW, Huang Y, Yao X (2011b) Electrophysiological properties of heteromeric TRPV4-C1 channels. Biochem Biophys Acta 1808:2789–2797

    Google Scholar 

  • Ma X, He D, Ru X, Chen Y, Cai Y, Bruce IC, Xia Q, Yao X, Jin J (2012) Apigenin, a plant-derive flavone, activates transient receptor potential vanilloid 4 cation channel. Br J Pharmacol 166:349–358

    Google Scholar 

  • Macaskill AF, Rinholm JE, Twelvetrees AE, Arancibia-Carcamo IL, Muir J, Fransson A, Aspenstrom P, Attwell D, Kittler JT (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61(4):541–555

    PubMed  CAS  Google Scholar 

  • Masuyama R, Mizuno A, Komori H, Kajiya H, Uekawa A, Kitaura H, Okabe K, Ohyama K, Komori T (2012) Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass. J Bone Mineral Res 27:1708–1721

    CAS  Google Scholar 

  • McEntagart M (2012) TRPV4 axonal neuropathy spectrum disorder. J Clin Neurosci 19:927–933

    PubMed  Google Scholar 

  • McEntagart ME, Reid SL, Irrthum A, Douglas JB, Eyre KE, Donaghy MJ, Anderson NE, Rahman N (2005) Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol 57:293–297

    PubMed  CAS  Google Scholar 

  • Muramatsu S, Wakabayashi M, Ohno T, Amano K, Ooishi R, Sugahara T, Shiojiri S, Tashiro K, Suzuki Y, Nishimura R, Kuhara S, Sugano S, Yoneda T, Matsuda A (2007) Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J Biol Chem 282:32158–32167

    PubMed  CAS  Google Scholar 

  • Nilius B, Voets T (2013) The puzzle of TRPV4 channelopathies. EMBO Rep 14(2):152–163

    PubMed  CAS  Google Scholar 

  • Nishimura G, Dai J, Lausch E, Unger S, Megarbané A, Kitoh H, Kim OH, Cho TJ, Bedeschi F, Benedicenti F, Mendoza-Londono R, Silengo M, Schmidt-Rimpler M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A (2010) Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet 152A(6):1443–1449

    PubMed  Google Scholar 

  • Nural MS, Diren HB, Sakarya O, Yalin T, Dağdemir A (2006) Kozlowski type spondylometaphyseal dysplasia: a case report with literature review. Diagn Interv Radiol 12:70–73

    PubMed  Google Scholar 

  • O’Conor CJ, Griffin TM, Liedtke W, Guilak F (2013) Increased susceptibility of TRPV4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis 72:300–304

    PubMed  Google Scholar 

  • Oates EC, Reddel S, Rodriguez ML, Gandolfo LC, Bahlo M, Hawke SH, Lamande SR, Clarke NF, North KN (2012) Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells. Brain 135:1714–1723

    PubMed  Google Scholar 

  • Obeidat M, Wain LV, Shrine N, Kalsheker N, Soler Artigas M, Repapi E, Burton PR, Johnson T, Ramasamy A, Zhao JH, Zhai G, Huffman JE, Vitart V, Albrecht E, Igl W, Hartikainen AL, Pouta A, Cadby G, Hui J, Palmer LJ, Hadley D, McArdle WL, Rudnicka AR, Barroso I, Loos RJ, Wareham NJ, Mangino M, Soranzo N, Spector TD, Gläser S, Homuth G, Völzke H, Deloukas P, Granell R, Henderson J, Grkovic I, Jankovic S, Zgaga L, Polašek O, Rudan I, Wright AF, Campbell H, Wild SH, Wilson JF, Heinrich J, Imboden M, Probst-Hensch NM, Gyllensten U, Johansson A, Zaboli G, Mustelin L, Rantanen T, Surakka I, Kaprio J, Jarvelin MR, Hayward C, Evans DM, Koch B, Musk AW, Elliott P, Strachan DP, Tobin MD, Sayers I, Hall IP, Consortium S (2011) A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample. PLoS ONE 6(5):e19382

    Google Scholar 

  • Pareyson D, Marchesi C, Salsano E (2009) Hereditary predominantly motor neuropathies. Curr Opin Neurol 22(5):451–459

    PubMed  Google Scholar 

  • Phan MN, Leddy HA, Votta BJ, Kumar S, Levy DS, Lipshutz DB, Lee SH, Liedtke W, Guilak F (2009) Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum 60:3028–3037

    PubMed  CAS  Google Scholar 

  • Phelps CB, Wang RR, Choo SS, Gaudet R (2010) Differential regulation of TRPV1, TRPV3, and TRPV4 sensitivity through a conserved binding site on the ankyrin repeat domain. J Biol Chem 285(1):731–740

    PubMed  CAS  Google Scholar 

  • Pochynyuk O, Zaika O, O’Neil RG, Mamenko M (2013) Novel insights into TRPV4 function in the kidney. Pflügers Arch 465:177–186

    PubMed  CAS  Google Scholar 

  • Reddel S, Ouvrier RA, Nicholson G, Dierick I, Irobi J, Timmerman V, Ryan MM (2008) Autosomal dominant congenital spinal muscular atrophy—a possible developmental deficiency of motor neurones? Neuromuscul Disord 18:530–555

    PubMed  CAS  Google Scholar 

  • Reilly MM, Murphy SM, Laurá M (2011) Charcot-Marie-Tooth disease. J Peripher Nerv Syst 16:1–14

    PubMed  Google Scholar 

  • Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T, Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH (2008) Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40(8):999–1003

    PubMed  CAS  Google Scholar 

  • Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D’Adamo P, Casari G (2002) Charcot-Marie-Tooth disease type 2C: a distinct genetic identity. Clinical and molecular characterization of the first European family. Neuromuscul Disord 12:399–404

    PubMed  CAS  Google Scholar 

  • Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, Rizzuto R, Hajnóczky G (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci USA 105(52):20728–20733

    PubMed  CAS  Google Scholar 

  • Sensenbrenner JA, Dorst JP, Hungerford DS (1974) Parastremmatic dwarfism. Birth Defects Orig Artic Ser 10:424–429

    PubMed  CAS  Google Scholar 

  • Shigematsu H, Sokabe T, Danev R, Tominaga M, Nagayama K (2010) A 3.5-nm structure of rat TRPV4 cation channel revealed by Zernike phase-contrast cryoelectron microscopy. J Biol Chem 285(15):11210–11218

    PubMed  CAS  Google Scholar 

  • Shin SH, Lee EJ, Hyun S, Chun J, Kim Y, Kang SS (2012) Phosphorylation on the Ser 824 residue of TRPV4 prefers to bind with F-actin than with microtubules to expand the cell surface area. Cell Signal 24(3):641–651

    PubMed  CAS  Google Scholar 

  • Shohat M, Lachman R, Gruber HE, Rimoin DL (1989) Brachyolmia: radiographic and genetic evidence of heterogeneity. Am J Med Genet 33:209–219

    PubMed  CAS  Google Scholar 

  • Smith PL, Maloney KN, Pothen RG, Clardy J, Clapham DE (2006) Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem 281:29897–29904

    PubMed  CAS  Google Scholar 

  • Stewart AP, Smith GD, Sandford RN, Edwardson JM (2010) Atomic force microscopy reveals the alternating subunit arrangement of the TRPP2-TRPV4 heterotetramer. Biophys J 99(3):790–797

    PubMed  CAS  Google Scholar 

  • Strotmann R, Schultz G, Plant TD (2003) Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. J Biol Chem 278:26541–26549

    PubMed  CAS  Google Scholar 

  • Strotmann R, Semtner M, Kepura F, Plant TD, Schöneberg T (2010) Interdomain interactions control Ca2+-dependent potentiation in the cation channel TRPV4. PLoS ONE 5(5):e10580

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, Lepore JJ, Willette RN (2012) An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 4(159):159ra148

    Google Scholar 

  • Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP, Chendrimada TP, Lashinger ESR, Gordon E, Evans L, Misajet BA, DeMarini DJ, Nation JH, Casillas LN, Marquis RW, Votta BJ, Sheardown SA, Xu X, Brooks DP, Laping NJ, Westfall TD (2008) N-((1S)-1-{[4-((2S)-2-{[2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanol)-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 1. J Pharmacol Exp Ther 326:432–442

    PubMed  CAS  Google Scholar 

  • Tian W, Fu Y, Garcia-Elias A, Fernández-Fernández JM, Vicente R, Kramer PL, Klein RF, Hitzemann R, Orwoll ES, Wilmot B, McWeeney S, Valverde MA, Cohen DM (2009) A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci USA 106(33):14034–14039

    PubMed  CAS  Google Scholar 

  • Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano I, Bertini E, Dionisi-Vici C, Nilius B, Zabel B, Superti-Furga A (2011) Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy? Am J Med Genet Part A 155:2860–2864

    CAS  Google Scholar 

  • van der Vleuten AJW, van Ravenswaaij-Arts CMA, Frijns CJM, Smits APT, Hageman G, Padberg GW, Kremer H (1998) 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

    PubMed  Google Scholar 

  • Vandewauw I, Owsianik G, Voets T (2013) Systematic and quantitative mRNA expression analysis of TRP channel genes at the single trigeminal and dorsal root ganglion level in mouse. BMC Neurosci 14:21

    PubMed  CAS  Google Scholar 

  • Vincent F, Duncton MA (2011) TRPV4 agonists and antagonists. Curr Top Med Chem 11(17):2216–2226

    PubMed  CAS  Google Scholar 

  • Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, Nilius B (2004) Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc Natl Acad Sci USA 101(1):396–401

    PubMed  CAS  Google Scholar 

  • Wang X, Schwarz TL (2009) The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell 136:163–174

    PubMed  CAS  Google Scholar 

  • Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, Vriens J, Cairns W, Wissenbach U, Prenen J, Flockerzi V, Droogmans G, Benham CD, Nilius B (2002) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem 277:13569–13577

    PubMed  CAS  Google Scholar 

  • Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, Laznik D, Kamenecka TM, Song X, Liedtke W, Mootha VK, Puigserver P, Griffin PR, Clapham DE, Spiegelman BM (2012) TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151:96–110

    PubMed  CAS  Google Scholar 

  • Yiu EM, Ryan MM (2012) Genetic axonal neuropathies and neuronopathies of pre-natal and infantile onset. J Peripher Nerv Syst 17(3):285–300

    PubMed  Google Scholar 

  • Zhu G, Investigators I, Gulsvik A, Bakke P, Ghatta S, Anderson W, Lomas DA, Silverman EK, Pillai SG (2009) Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum Mol Genet 18(11):2053–2062

    PubMed  CAS  Google Scholar 

  • Zimoń M, Baets J, Auer-Grumbach M, Berciano J, Garcia A, Lopez-Laso E, Merlini L, Hilton-Jones D, McEntagart M, Crosby AH, Barisic N, Boltshauser E, Shaw CE, Landouré G, Ludlow CL, Gaudet R, Houlden H, Reilly MM, Fischbeck KH, Sumner CJ, Timmerman V, Jordanova A, Jonghe PD (2010) Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain 133(Pt 6):1798–1809

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University, Baltimore, MD, 21205, USA

    Jeremy M. Sullivan, Thomas E. Lloyd & Charlotte J. Sumner

  2. Department of Neuroscience, Johns Hopkins University, Baltimore, MD, 21205, USA

    Thomas E. Lloyd & Charlotte J. Sumner

Authors
  1. Jeremy M. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas E. Lloyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte J. Sumner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy M. Sullivan .

Editor information

Editors and Affiliations

  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Sullivan, J.M., Lloyd, T.E., Sumner, C.J. (2014). Hereditary Channelopathies Caused by TRPV4 Mutations. In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_21

Download citation

Publish with us

Policies and ethics

Search

Navigation