Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4

Deng, Han Xiang; Klein, Christopher J.; Yan, Jianhua; Shi, Yong; Wu, Yanhong; Fecto, Faisal; Yau, Hau Jie; Yang, Yi; Zhai, Hong; Siddique, Nailah; Hedley‐Whyte, E. Tessa; DeLong, Robert; Martina, Marco; Dyck, Peter J.; Siddique, Teepu

doi:10.1038/ng.509

Cited by 232 publications

(224 citation statements)

References 31 publications

(46 reference statements)

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“…We then examined the binding of the R232C, R269H, R315W and R316H mutants, identified in CMT2C and other diseases [7][8][9]25 . All of these mutants, except for R232C, showed significantly decreased binding to PI(4,5)P 2 -containing liposomes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The cells were maintained at À 30 mV, and the currents were elicited by slow voltage ramps (from À 100 mV to þ 100 mV, 0.6 s duration). The standard extracellular (bath) solution contained 100 mM NaCl, 6 mM KCl, 2 mM MgCl 2 , 1.5 mM CaCl 2 , 10 mM glucose and 10 mM HEPES (pH 7.38 adjusted with NaOH, and osmolality adjusted to 300 mmol kg À 1 with sucrose) 7 . The standard intracellular (pipette) solution contained 140 mM CsCl, 2 mM MgCl 2 , 10 mM EGTA, 2 mM Na 2 ATP, 0.1 mM NaGTP and 10 mM HEPES (pH 7.28 adjusted with CsOH, and osmolality adjusted to 298 mmol kg À 1 with sucrose) 7 .…”

Section: Methodsmentioning

confidence: 99%

“…The mutations in TRPV4 are the most recently identified CMT subtype, in terms of genetic locus 1,2 . Previous studies have suggested that the gain-of-function mutations of TRPV4 in these diseases, which exhibit increased basal and maximum Ca 2 þ channel activities, are clustered within the TRPV4 ARD and affect arginine residues, especially at the R232C, R269C/H, R315W, R316C/H positions [7][8][9][10] . The increased Ca 2 þ influx and subsequent Ca 2 þ overload associated with these mutations are thought to be the cause of cell death, and have been proposed as a mechanism for peripheral axonal degeneration in TRPV4-dependent neuropathies 9,10 .…”

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TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

et al. 2014

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Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot-Marie-Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P 2 , and the molecular-dynamics simulations revealed the PI(4,5)P 2 -binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P 2 . Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P 2 binding and PI(4,5)P 2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P 2 normalize the channel activity in TRPV4.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

et al. 2014

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“…Mutations in the human TRPV4 gene have been identified as the direct cause of divergent hereditary diseases, including skeletal dysplasias, spinal muscular atrophy, and CharcotMarie-Tooth disease type 2C (36)(37)(38)(39)(40)(41). Although the exact role of TRPV4 in the etiology of these clinically diverse diseases is unknown, it appears that many disease-causing mutations lead to gain of TRPV4 function (41).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

Everaerts

Zhen²,

Ghosh

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

345

305

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Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4 −/− mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4 −/− mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction. transient receptor potential channels | urothelium

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“…In our original study, we tested two mutations, R316C and R269H, which were identified in the original SPSMA and CMT2C families, respectively (6). We found that in HEK293 cells, mutant TRPV4 had a physiological localization on the plasma membrane similar to wild-type TRPV4 (wtTRPV4).…”

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confidence: 99%

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

Fecto

Shi

Huda

et al. 2011

Journal of Biological Chemistry

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Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a "gain of function" mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.Scapuloperoneal spinal muscle atrophy (SPSMA), congenital distal spinal muscle atrophy (CDSMA), and Charcot-MarieTooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type 2, HMSN IIC) are phenotypically heterogeneous and dominantly inherited disorders involving topographically distinct muscles and nerves (1, 2). Genetic linkage analysis mapped the disease loci to an overlapping region at 12q24 (3-5). Recently, it has been shown that these three axonal neuropathies are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V (vanilloid), member 4 (TRPV4) 3 (6 -8). To date, seven mutations in TRPV4 have been identified in 15 families with axonal neuropathies (6 -10). Functional studies, however, yielded divergent hypotheses about the pathogenic mechanism of the diseases (6 -8, 10).In our original study, we tested two mutations, R316C and R269H, which were identified in the original SPSMA and CMT2C families, respectively (6). We found that in HEK293 cells, mutant TRPV4 had a physiological localization on the plasma membrane similar to wild-type TRPV4 (wtTRPV4). Calcium imaging showed that mutant TRPV4 had significantly increased calcium channel activity, at both basal and activated levels when compared with wtTRPV4. These findings were consistent with electrophysiological recordings, which showed a higher TRPV4 conductance in HEK293 cells expressing the R269H mutant compared with wtTRPV4. In another study, Landouré et al. (8) showed similar results in HEK293 cells and Xenopus laevis oocytes with R269H and R269C mutations. Furthermore, mutant TRPV4-mediated cytotoxicity was observed in transfected HEK293 cells and dorsal root ganglion neurons. This cytotoxicity was related to increased intracellular calcium concentrations (8). More recently, we have also shown that two other TRPV4 mutants (R232C and R316H) localize appropriately and cause reversible and toxic hypercalcemia in HEK293 and HeLa c...

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Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4

Cited by 232 publications

References 31 publications

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

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