Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.
Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.
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DOI：
10.1002/ana.24612
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发表时间：
2016-04
影响因子：
11.2
通讯作者：
Takashima, Hiroshi
中科院分区：
文献类型：
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作者：
Higuchi, Yujiro;Hashiguchi, Akihiro;Yuan, Junhui;Yoshimura, Akiko;Mitsui, Jun;Ishiura, Hiroyuki;Tanaka, Masaki;Ishihara, Satoshi;Tanabe, Hajime;Nozuma, Satoshi;Okamoto, Yuji;Matsuura, Eiji;Ohkubo, Ryuichi;Inamizu, Saeko;Shiraishi, Wataru;Yamasaki, Ryo;Ohyagi, Yasumasa;Kira, Jun-ichi;Oya, Yasushi;Yabe, Hayato;Nishikawa, Noriko;Tobisawa, Shinsuke;Matsuda, Nozomu;Masuda, Masayuki;Kugimoto, Chiharu;Fukushima, Kazuhiro;Yano, Satoshi;Yoshimura, Jun;Doi, Koichiro;Nakagawa, Masanori;Morishita, Shinichi;Tsuji, Shoji;Takashima, Hiroshi
本研究的目的是确定常染色体隐性遗传(AR)患者中夏科-玛丽-图思(CMT)病的新病因。为了有效地识别AR-CMT的新致病基因，我们使用全外显子测序技术分析了303名无关的日本CMT患者，并提取了多个患者共有的隐性变异/基因。我们对354例CMT患者进行了新发现的膜金属内肽酶(MME)基因突变筛查。我们对10名MME突变患者进行了临床、遗传学、病理学和放射学检查。我们在10例患者中发现了MME的隐性突变。MME基因编码Neprilysin(NEP)，这是众所周知的最突出的β-淀粉样蛋白(Aβ)降解酶之一。所有患者都有与迟发性轴索神经病一致的相似表型。他们表现为四肢肌肉无力、萎缩和感觉障碍。所有MME突变都可能是功能丧失突变，我们证实了NEP蛋白在周围神经中的表达缺失/减少。没有患者出现痴呆症状，1例患者在匹兹堡复合B正电子发射断层扫描中未显示过多的A-β。我们的结果表明，MME功能丧失突变是日本成人起病AR-CMT2最常见的原因，我们建议将这种新疾病命名为AR-CMT2T。功能丧失的MME突变不会导致早发性阿尔茨海默病。识别与AR-CMT相关的MME突变有助于提高分子诊断率和对CMT分子机制的认识。Ann Neurol 2016；79：659-672
The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT. To efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging. Our results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
82.9
作者：
Iwata, N;Tsubuki, S;Saido, TC
通讯作者：
Saido, TC
影响因子：
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作者：
Fischer, HS;Zernig, G;Saria, A
通讯作者：
Saria, A
影响因子：
3.4
作者：
KIOUSSI, C;MAMALAKI, A;MATSAS, R
通讯作者：
MATSAS, R
影响因子：
4.6
作者：
Iwata, Nobuhisa;Sekiguchi, Misaki;Hattori, Yoshino;Takahashi, Akane;Asai, Masashi;Ji, Bin;Higuchi, Makoto;Staufenbiel, Matthias;Muramatsu, Shin-ichi;Saido, Takaomi C.
通讯作者：
Saido, Takaomi C.