title: Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashiguchi
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Junhui
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of Cardiovascular medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishihara
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Tanabe
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nozuma
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Matsuura
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ohkubo
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Inamizu
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shiraishi
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
authors.affiliation: Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oya
authors.affiliation: Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Yabe
authors.affiliation: Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nishikawa
authors.affiliation: Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Tobisawa
authors.affiliation: Department of Neurology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Matsuda
authors.affiliation: Department of Neurology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Department of Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kugimoto
authors.affiliation: Department of Home-Care Promotion, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Department of Neurology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yano
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Director of North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takashima
mesh_terms: D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015260:Neprilysin / Q000235:genetics*; D010641:Phenotype
chemical_list: D015260:Neprilysin