title: A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy.
abstract: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy.
authors.affiliation: Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Seoul, Korea.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Jaesoon
authors.initials: J
authors.lastname: Joo
authors.affiliation: Department of Biological Science, Kongju National University, Gongju, Korea.
authors.forename: Young Se
authors.initials: YS
authors.lastname: Hyun
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Geon
authors.initials: G
authors.lastname: Kwak
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Yu-Ri
authors.initials: YR
authors.lastname: Choi
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ha Kyung
authors.initials: HK
authors.lastname: Yeo
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Jwa
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Neuroscience Center, Samsung Medical Center, Seoul, Korea.
authors.forename: Eun Ja
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Won Min
authors.initials: WM
authors.lastname: Mo
authors.affiliation: Department of Biological Science, Kongju National University, Gongju, Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Department of Biological Science, Kongju National University, Gongju, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Radiology, Ewha Womans University, School of Medicine, Seoul, Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Ewha Womans University, School of Medicine, Seoul, Korea.
authors.forename: Heasoo
authors.initials: H
authors.lastname: Koo
authors.affiliation: Department of Physiology, College of Medicine, Dong-A University, Busan, Korea.
authors.forename: Hwan Tae
authors.initials: HT
authors.lastname: Park
authors.affiliation: Department of Biological Science, Kongju National University, Gongju, Korea.
authors.forename: Ki Wha
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Neuroscience Center, Samsung Medical Center, Seoul, Korea.
authors.forename: Byung-Ok
authors.initials: BO
authors.lastname: Choi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020090:Chromosome Segregation; D003198:Computer Simulation; D003711:Demyelinating Diseases / Q000235:genetics*; D055724:Electrophysiological Phenomena; D005190:Family; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D007866:Leg / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D018996:Myelin P2 Protein / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013497:Sural Nerve / Q000473:pathology / Q000503:physiopathology
chemical_list: D018996:Myelin P2 Protein; C560555:PMP2 protein, human
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