Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2

Ann Neurol. 2016 Apr;79(4):659-72. doi: 10.1002/ana.24612.

Yujiro Higuchi ¹, Akihiro Hashiguchi ¹, Junhui Yuan ¹, Akiko Yoshimura ¹, Jun Mitsui ², Hiroyuki Ishiura ², Masaki Tanaka ², Satoshi Ishihara ¹ ³, Hajime Tanabe ¹, Satoshi Nozuma ¹, Yuji Okamoto ¹, Eiji Matsuura ¹, Ryuichi Ohkubo ¹ ⁴, Saeko Inamizu ⁵, Wataru Shiraishi ⁵, Ryo Yamasaki ⁵, Yasumasa Ohyagi ⁵, Jun-ichi Kira ⁵, Yasushi Oya ⁶, Hayato Yabe ⁷, Noriko Nishikawa ⁷, Shinsuke Tobisawa ⁸, Nozomu Matsuda ⁹, Masayuki Masuda ¹⁰, Chiharu Kugimoto ¹¹, Kazuhiro Fukushima ¹², Satoshi Yano ¹³, Jun Yoshimura ¹⁴, Koichiro Doi ¹⁴, Masanori Nakagawa ¹⁵, Shinichi Morishita ¹⁴, Shoji Tsuji ², Hiroshi Takashima ¹

Affiliations

1 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
2 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
3 Department of Cardiovascular medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
4 Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
5 Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
6 Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
7 Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan.
8 Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
9 Department of Neurology, Fukushima Medical University, Fukushima, Japan.
10 Department of Neurology, Tokyo Medical University, Tokyo, Japan.
11 Department of Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
12 Department of Home-Care Promotion, Shinshu University School of Medicine, Matsumoto, Japan.
13 Department of Neurology, Showa University School of Medicine, Tokyo, Japan.
14 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
15 Director of North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PMID: 26991897 DOI: 10.1002/ana.24612

Abstract

Objective: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT.

Methods: 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.

Results: 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.

Interpretation: 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.

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