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


Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C1,2. We mapped SPSMA and CMT2C risk loci to 12q24.1–q24.31 with an overlapping region between the two diseases3,4. Further analysis reduced the CMT2C risk locus to a 4-Mb region5. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders.

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Figure 1: Pathology of an individual with SPSMA.
Figure 2: TRPV4 mutations in SPSMA and CMT2C pedigrees.
Figure 3: Localization of wild-type and mutant TRPV4 on the plasma membrane.
Figure 4: Effect of mutations on TRPV4 activity when stimulated with 4αPDD.
Figure 5: Effect of mutations on TRPV4 activity when stimulated with hypotonic solution.
Figure 6: Whole-cell recordings of TRPV4 currents from transfected HEK293 cells.

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The authors acknowledge the support from the National Institute of Neurological Disorders and Stroke (NS050641), the Les Turner ALS Foundation, the Vena E. Schaff ALS Research Fund, the Harold Post Research Professorship, the Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, the Help America Foundation, the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship and the Epilepsy Foundation. We thank R. J. Miller and A. Belmadani for help with the calcium imaging studies and J. Caliendo for proofreading this manuscript.

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Authors and Affiliations



T.S., H.-X.D. and C.J.K. conceived this project. H.-X.D., J.Y., Y.S., Y.W., Y.Y. and H.Z. did the sequencing analysis. F.F., Y.S. and H.-X.D. performed the calcium imaging analysis. H.-J.Y. and M.M. performed the whole-cell patch-clamp recordings. N.S. collected family information and samples. E.T.H.-W. did pathological analysis. C.J.K., R.D., P.J.D. and T.S. did clinical studies. H.-X.D., C.J.K., M.M. and T.S. analyzed the data and wrote the paper.

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Correspondence to Han-Xiang Deng or Teepu Siddique.

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Deng, HX., Klein, C., Yan, J. et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 42, 165–169 (2010).

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