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.

Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy / E. Monfrini, L. Straniero, S. Bonato, G. Monzio Compagnoni, A. Bordoni, R. Dilena, P. Rinchetti, R. Silipigni, D. Ronchi, S. Corti, G.P. Comi, N. Bresolin, S. Duga, A. Di Fonzo. - In: PARKINSONISM & RELATED DISORDERS. - ISSN 1353-8020. - (2019 Mar 01). [Epub ahead of print] [10.1016/j.parkreldis.2019.02.045]

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

E. Monfrini
Primo
;
L. Straniero
Secondo
;
S. Bonato;G. Monzio Compagnoni;A. Bordoni;P. Rinchetti;R. Silipigni;D. Ronchi;S. Corti;G.P. Comi;N. Bresolin;S. Duga
Penultimo
;
A. Di Fonzo
Ultimo
2019-03-01

Abstract

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.
Hereditary Ataxia; Neurofascin; Neuropathy; NFASC; Nodopathy; Neurology; Geriatrics and Gerontology; Neurology (clinical)
Settore MED/26 - Neurologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
Monfrini 2019 2.pdf

embargo fino al 28/05/2020

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 782.3 kB
Formato Adobe PDF
782.3 kB Adobe PDF Visualizza/Apri
1-s2.0-S1353802019300914-main.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 2.27 MB
Formato Adobe PDF
2.27 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/634672
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 14
social impact