An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families
An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families
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DOI：
10.1038/s10038-022-01019-y
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发表时间：
2022-01-28
影响因子：
3.5
通讯作者：
Takashima, Hiroshi
中科院分区：
文献类型：
--
作者：
Ando, Masahiro;Higuchi, Yujiro;Takashima, Hiroshi
背景和目的神经丝基因的突变与几种神经肌肉疾病有关。2016年，神经丝蛋白重链（NEFH）基因被确定为腓骨肌萎缩症2型CC（CMT2CC）的致病基因，其毒性功能获得机制由3 '非翻译区（UTR）中的隐蔽淀粉样蛋白生成元件（CAE）的翻译和聚集引起。但在日本，NEFH相关的临床和遗传谱仍不清楚。方法我们分析了来自我们内部全外显子组测序数据的NEFH基因的所有变体，这些数据来自日本全国神经肌肉疾病患者，包括腓骨肌萎缩症（CMT）和脊髓性肌萎缩症（SMA）。结果我们在3个临床诊断为CMT的NEFH家系和1个SMA家系中发现了c.3017dup（p.Pro1007Alafs*56）变异。除了典型的周围神经病变的患者，锥体束的迹象，观察到一个CMT患者。而SMA患者表现为肱三头肌和股四头肌的严重特征性无力。所有这四个家庭居住在鹿儿岛县的日本，和以下单倍型分析强烈建议的创始人效应。解释这是关于NEFH创始突变的原始报告。我们研究中的临床多样性，包括CMT（伴或不伴锥体束征）和SMA，表明广泛累及周围神经、前角细胞或两者。我们的发现拓宽了NEFH相关疾病的表型谱。
Background and aims Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3 ' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. Methods We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). Results We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. Interpretation This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.