A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.
A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.
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DOI：
10.1002/ana.21728
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发表时间：
2009-12
影响因子：
11.2
通讯作者：
Scherer, Steven S.
中科院分区：
文献类型：
--
作者：
Yum, Sabrina W.;Zhang, Junxian;Mo, Katie;Li, Jian;Scherer, Steven S.
为了报告第一例NEFL的纯合子隐性突变，NEFL是编码神经细丝的轻亚单位(NFL)的基因。对所有家庭成员的临床和电生理数据进行了评估，并对1名患病儿童的腓肠神经活检进行了免疫组织化学和电子显微镜检查。在已建立的细胞培养系统中，对突变蛋白形成细丝的能力进行了表征。五个兄弟姐妹中有四个从童年早期就开始患上严重的进行性神经病。一系列神经传导研究显示，随着年龄的增长，波幅逐渐降低，并且在所有年龄段都明显减慢。3名儿童视觉诱发反应减慢，表明中枢神经系统轴突参与亚临床。所有四个受影响的儿童都是NEFL基因中谷氨酸210(E210X)无意义突变的纯合子；父母都是杂合携带者。患者16岁时的腓肠神经活检显示有髓轴突数量明显减少；其余的有髓轴突较小，缺乏中间丝。E210X突变体蛋白不形成中间丝网络，也不干扰野生型人NFL在Sw-13 VIM细胞中的丝状形成。这是隐性NEFL突变的第一次证明，这种突变似乎会导致简单的功能丧失，导致具有独特特征的严重的早发性轴索神经病。这些结果证实了神经丝是轴突口径和传导速度的主要决定因素，并首次证明了神经丝是维持有髓三叉神经节轴突所必需的。
To report the first cases of homozygous recessive mutations in NEFL, the gene that encodes the light subunit of neurofilaments (NFL). Clinical and electrophysiologic data of all family members were evaluated, and a sural nerve biopsy from one affected child was examined by immunohistochemistry and electron microscopy. The ability of the mutant protein to form filaments was characterized in an established cell culture system. Four of five siblings developed a severe, progressive neuropathy beginning in early childhood. Serial nerve conduction studies showed progressively reduced amplitudes with age, and pronounced slowing at all ages. Visual evoked responses were slowed in three children, indicating that CNS axons were subclinically involved. All four affected children were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL gene; both parents were heterozygous carriers. A sural nerve biopsy from an affected patient at age 16 revealed markedly reduced numbers of myelinated axons; the remaining myelinated axons were small and lacked intermediate filaments. The E210X mutant protein did not form an intermediate filament network, and did not interfere with the filament formation by wild type human NFL in SW-13 vim- cells. This is the first demonstration of a recessive NEFL mutation, which appears to cause a simple loss-of-function, resulting in a severe, early-onset axonal neuropathy with unique features. These results confirm that neurofilaments are the main determinant of axonal caliber and conduction velocity, and demonstrate for the first time that neurofilaments are required for the maintenance of myelinated PNS axons.
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影响因子：
14.5
作者：
Fabrizi, Gian Maria;Cavallaro, Tiziana;Rizzuto, Nicolo'
通讯作者：
Rizzuto, Nicolo'
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作者：
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通讯作者：
SAMORAJS.T
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作者：
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通讯作者：
CLEVELAND, DW
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作者：
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通讯作者：
Lazzarini, RA
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作者：
ARBUTHNOTT, ER;BOYD, IA;KALU, KU
通讯作者：
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