A new mutation in FIG4 causes a severe form of CMT4J involving TRPV4 in the pathogenic cascade

Benoit J. Gentil, Erin O'Ferrall, Colin Chalk, Luis Fernando Santana, Heather D. Durham, Rami Massie

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Mutations in FIG4, coding for a phosphoinositol(3,5) bisphosphate 5' phosphatase and involved in vesicular trafficking and fusion, have been shown causing a recessive form of Charcot- Marie-Tooth (CMT). We have identified a novel intronic mutation in the FIG4 in a wheel-chair bound patient presenting with a severe form of CMT4J and provide a longitudinal study. Investigations indicated a demyelinating sensorimotor polyneuropathy with diffuse active denervation and severe axonal loss. Genetic testing revealed that the patient is heterozygous for 2 FIG4 mutations, p.I41T and a T > G transversion at IVS17 - 10, the latter predicted to cause a splicing defect. FIG4 was severely diminished in patient's fibroblasts indicating loss-of-function. Consistent with FIG4's function in phosphoinositol homeostasis and vesicular trafficking, fibroblasts contained multiple large vacuoles and vesicular organelles were abnormally dispersed. FIG4 deficiency has implications for turnover of membrane proteins. The transient receptor cation channel, TRPV4, accumulated at the plasma membrane of patient's fibroblasts due to slow turnover. Knocking down Fig4 in murine cultured motor neurons resulted in vacuolation and cell death. Inhibiting TRPV4 activity significantly preserved viability, although not correcting vesicular trafficking. In conclusion, we demonstrate a new FIG4 intronic mutation and, importantly, a functional interaction between FIG4 and TRPV4.

Original languageEnglish (US)
Pages (from-to)789-799
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Issue number9
StatePublished - Jan 1 2017
Externally publishedYes


  • Charcot-Marie-Tooth disease
  • Endosomes
  • FIG4
  • Motor neurons
  • Phosphoinositol(3,5) biphosphate
  • TRPV4

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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