Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease
Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease
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DOI：
10.1093/brain/awg059
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发表时间：
2003-03-01
期刊：
影响因子：
14.5
通讯作者：
Timmerman, V
中科院分区：
文献类型：
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作者：
Jordanova, A;De Jonghe, P;Timmerman, V
神经丝轻链多肽（NEFL）是神经元中含量最丰富的细胞骨架成分之一。NEFL基因突变最近被报道为与染色体8 p21连锁的常染色体显性Charcot-Marie-Tooth 2 E型（CMT 2 E）的原因。为了研究NEFL突变的频率和表型结果，我们筛选了323例CMT或相关周围神经病变患者。我们检测到六个疾病相关的错义突变和一个3 bp的框内缺失聚集在NEFL蛋白的功能定义的结构域。患者具有早期发作并且通常具有严重的临床表型。电生理检查显示中度至重度神经传导速度减慢。我们报告的第一个神经活检CMT患者与新生错义突变NEFL，并发现轴突病理轴突再生簇和洋葱球的形成。我们的研究结果提供了进一步的证据表明，在CMT中观察到的临床变异取决于基因突变和特定类型的突变，我们还建议，NEFL突变需要考虑在散发或显性遗传CMT患者的分子评价。
Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.