The gene for HMSN2C maps to 12q23-24

Klein, Christopher J.; Cunningham, J. M.; Atkinson, E. J.; Schaid, Daniel J.; Hebbring, Scott J.; Anderson, Stephanie A.; Klein, D M; Litchy, William J.; Thibodeau, SN; Dyck, Peter J.

doi:10.1212/01.wnl.0000055900.30217.ea

Cited by 72 publications

(46 citation statements)

References 27 publications

(21 reference statements)

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“…Furthermore, incomplete penetrance or markedly variable expression may also obscure the genetic cause as seen in our original kindred with R269H mutation where repeated clinical examinations over time including specialized nerve conductions were required to identify very mildly affected persons and hence the accurately diagnosed affected status. 2,5,8 Therefore penetrance should only be determined close to the end of life as symptoms among some may not occur until the eighth decade of life.…”

Section: Confocal Microscopy Was Performed Using Hek293 Cells Transfementioning

confidence: 99%

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies

Klein

Shi²,

Fecto³

et al. 2011

Neurology

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Objective: To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism.Methods: A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca 2ϩ channel analysis, and cell viability assay with or without channel blockade.Results: Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca 2ϩ levels and reversible cell death by the TRPV channel antagonist, ruthenium red. Conclusion:

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Section: Confocal Microscopy Was Performed Using Hek293 Cells Transfementioning

confidence: 99%

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies

Klein

Shi²,

Fecto³

et al. 2011

Neurology

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“…CMT has been classified into two types: CMT1 and CMT2, the demyelinating and axonal forms, respectively. CMT2 has been further divided into nine subgroups by linkage studies (Takashima et al 1999;Mersiyanova et al 2000;Ismailov et al 2001;Antonellis et al 2003;Klein et al 2003;Verhoeven et al 2003;Nelis et al 2004;Tang et al 2004;Zuchner et al 2004). Distal hereditary motor neuropathy (HMN) is an exclusively motor neuropathy but is also a clinically and genetically heterogeneous neuropathy.…”

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confidence: 99%

Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy

et al. 2005

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Heat shock protein 27 (HSP27) belongs to a family of small heat shock proteins that play significant roles in the cellular stress response and are also involved in the control of protein-protein interactions as chaperons. Mutation in HSP27 has been identified as the cause of axonal Charcot-Marie-Tooth disease (CMT) and distal hereditary motor neuropathy (HMN). Heat shock protein 22 (HSP22) is a molecular counterpart of HSP27, and its mutation is another cause of distal HMN. We screened the mutation of HSP27 and HSP22 in 68 Japanese patients with axonal CMT or unclassified CMT and six Japanese patients with distal HMN. We detected a heterozygous P182S mutation of HSP27 in a patient with distal HMN, but we found no mutations in HSP22. Mutation in HSP27 may impair the formation of the stable neurofilament network that is indispensable for the maintenance of peripheral nerves.

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“…Genetic linkage analysis mapped the disease loci to an overlapping region at 12q24 (3)(4)(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).…”

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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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The gene for HMSN2C maps to 12q23-24

Abstract: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

Cited by 72 publications

References 27 publications

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies

Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy

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

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