Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy

Edoardo Monfrini, Letizia Straniero, Sara Bonato, Giacomo Monzio Compagnoni, Andreina Bordoni, Robertino Dilena, Paola Rinchetti, Rosamaria Silipigni, Dario Ronchi, Stefania Corti, Giacomo P. Comi, Nereo Bresolin, Stefano Duga, Alessio Di Fonzo

Research output: Contribution to journalArticlepeer-review


Introduction: Neurofascin, encoded by NFASC, is a transmembrane protein that plays an essential role in nervous system development and node of Ranvier function. Anti-Neurofascin autoantibodies cause a specific type of chronic inflammatory demyelinating polyneuropathy (CIDP) often characterized by cerebellar ataxia and tremor. Recently, homozygous NFASC mutations were recently associated with a neurodevelopmental disorder in two families. Methods: A combined approach of linkage analysis and whole-exome sequencing was performed to find the genetic cause of early-onset cerebellar ataxia and demyelinating neuropathy in two siblings from a consanguineous Italian family. Functional studies were conducted on neurons from induced pluripotent stem cells (iPSCs) generated from the patients. Results: Genetic analysis revealed a homozygous p.V1122E mutation in NFASC. This mutation, affecting a highly conserved hydrophobic transmembrane domain residue, led to significant loss of Neurofascin protein in the iPSC-derived neurons of affected siblings. Conclusions: The identification of NFASC mutations paves the way for genetic research in the developing field of nodopathies, an emerging pathological entity involving the nodes of Ranvier, which are associated for the first time with a hereditary ataxia syndrome with neuropathy.

Original languageEnglish
Pages (from-to)66-72
JournalParkinsonism and Related Disorders
Publication statusPublished - Jan 1 2019


  • Hereditary Ataxia
  • Neurofascin
  • Neuropathy
  • Nodopathy

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology


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