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.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Parkinsonism Relat Disord. 2019 Jun;63:66-72. doi: 10.1016/j.parkreldis.2019.02.045. Epub 2019 Mar 1.
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.
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.
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.
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.
神经束蛋白（NFASC）编码的神经束蛋白是一种跨膜蛋白，在神经系统发育和郎飞结功能中起着至关重要的作用。抗神经束蛋白自身抗体引起一种特定类型的慢性炎症性脱髓鞘性多发性神经病（CIDP），常伴有小脑性共济失调和震颤。最近，NFASC 纯合突变与两个家族的神经发育障碍有关。
对来自一个意大利血缘家族的两个有血缘关系的兄弟姐妹的早发性小脑性共济失调和脱髓鞘性神经病进行连锁分析和全外显子组测序的联合方法，以寻找遗传病因。对患者诱导多能干细胞（iPSC）衍生的神经元进行功能研究。
遗传分析显示 NFASC 中的纯合 p.V1122E 突变。该突变影响高度保守的疏水性跨膜结构域残基，导致受影响的兄弟姐妹的 iPSC 衍生神经元中神经束蛋白的显著丢失。
NFASC 突变的鉴定为结节病的新兴病理学实体（涉及郎飞结）的发展领域的遗传研究铺平了道路，郎飞结与以前与神经病相关的遗传性共济失调综合征首次相关。
