Edoardo Monfrini1, Letizia Straniero2, Sara Bonato1, Giacomo Monzio Compagnoni1, Andreina Bordoni1, Robertino Dilena3, Paola Rinchetti1, Rosamaria Silipigni4, Dario Ronchi1, Stefania Corti1, Giacomo P Comi1, Nereo Bresolin1, Stefano Duga2, Alessio Di Fonzo5. 1. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy; Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 2. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 3. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurofisiopatologia Pediatrica, UOC Neurofisiopatologia, Milan, Italy. 4. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Laboratory of Medical Genetics, Milan, Italy. 5. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy; Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Electronic address: alessio.difonzo@policlinico.mi.it.
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.
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.
Authors: Alina Kurolap; Florian Kreuder; Claudia Gonzaga-Jauregui; Morasha Plesser Duvdevani; Tamar Harel; Luna Tammer; Baozhong Xin; Somayeh Bakhtiari; James Rice; Clare L van Eyk; Jozef Gecz; Jean K Mah; Derek Atkinson; Heidi Cope; Jennifer A Sullivan; Alon M Douek; Daniel Colquhoun; Jason Henry; Donald Wlodkowic; Yesim Parman; Ayşe Candayan; Elif Kocasoy-Orhan; Anat Ilivitzki; Shiri Soudry; Rina Leibu; Fabian Glaser; Valerie Sency; Gil Ast; Vandana Shashi; Michael C Fahey; Esra Battaloğlu; Albena Jordanova; Vardiella Meiner; A Micheil Innes; Heng Wang; Orly Elpeleg; Michael C Kruer; Jan Kaslin; Hagit Baris Feldman Journal: Am J Hum Genet Date: 2022-02-01 Impact factor: 11.043
Authors: Claire R Quilter; Kerry M Harvey; Julien Bauer; Benjamin M Skinner; Maria Gomez; Manu Shrivastava; Andrew M Doel; Saikou Drammeh; David B Dunger; Sophie E Moore; Ken K Ong; Andrew M Prentice; Robin M Bernstein; Carole A Sargent; Nabeel A Affara Journal: FASEB Bioadv Date: 2021-02-05