Abstract
Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot–Marie–Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown. In this study, we screened for TRPV4 mutations in a well-characterized USA cohort of 62 unrelated CMT2 patients without mutations in MFN2, GARS, NEFL, and GDAP1. All 15 coding exons of TRPV4 were analyzed by Sanger-sequencing. Clinical features of TRPV4-linked patients were compared with those lacking TRPV4 mutations. We identified two TRPV4 mutations in two patients. A TRPV4-R316C was identified in a patient with family history, while a TRPV4-R269C in an apparently sporadic case. Marked clinical variations were observed in the patients with TRPV4 mutations. Our data suggest that TRPV4-linked CMT2C accounts for a sizable fraction in this USA cohort of CMT2; it has a wide phenotypic spectrum, and vocal cord paralysis, scapular weakness and wasting, skeletal dysplasia, and hearing loss are suggestive signs for TRPV4-linked CMT2C.
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Acknowledgements
This study was supported by NIH (NS078287, NS099623 to H.-X.D., and U54NS065712 to M.E.S). M.E.S is also supported by the MDA and CMTA.
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H-XD, TS, and MES designed this study. SD, YS, LZ, TS, and H-XD performed sequencing analysis. SMEF collected clinical information. MES performed clinical studies. SD, H-XD, TS, and MES analyzed the data and wrote the paper.
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Dr. Michael E. Shy is a consultant for Alnylam, Inflectis, and Acceleron. The other authors declare no competing financial interests.
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Ethical approval was obtained from the University of Iowa (Iowa City, IA) and University of Wisconsin (UW; Madison, WI), and written informed assent/consent was provided by participants under a protocol approved by the ethics board of the NIH Rare Diseases Clinical Research Network (Protocol INC6611).
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Written informed consent was obtained from all participants involved in this study.
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Deng, S., Feely, S.M.E., Shi, Y. et al. Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot–Marie–Tooth Disease Type 2. Neuromol Med 22, 68–72 (2020). https://doi.org/10.1007/s12017-019-08564-4
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DOI: https://doi.org/10.1007/s12017-019-08564-4