Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy

Ilaria Vaccari, Antonietta Carbone, Stefano Carlo Previtali, Yevgeniya A. Mironova, Valeria Alberizzi, Roberta Noseda, Cristina Rivellini, Francesca Bianchi, Ubaldo Del Carro, Maurizio D'Antonio, Guy M. Lenk, Lawrence Wrabetz, Roman J. Giger, Miriam H. Meisler, Alessandra Bolino

Research output: Contribution to journalArticlepeer-review


Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P2 levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/ PtdIns(3,5)P2-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronaland axonal degeneration. Incontrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy.

Original languageEnglish
Article numberddu451
Pages (from-to)383-396
Number of pages14
JournalHuman Molecular Genetics
Issue number2
Publication statusPublished - Jan 15 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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