Open AccessA Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy
Author(s) -
Young Bin Hong,
Jinho Joo,
Young Se Hyun,
Geon Kwak,
Yongju Choi,
Ha Kyung Yeo,
Dong Hwan Jwa,
Eun Ja Kim,
Won Min Mo,
Soo Hyun Nam,
Sung Min Kim,
Jeong Hyun Yoo,
Heasoo Koo,
Hwan Tae Park,
Ki Wha Chung,
Byung Ok Choi
Publication year - 2016
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1005829
Subject(s) - biology , peripheral myelin protein 22 , myelin , sural nerve , mutation , peripheral neuropathy , genetic heterogeneity , atrophy , exome sequencing , genetically modified mouse , genetics , pathology , phenotype , transgene , anatomy , neuroscience , gene , medicine , endocrinology , central nervous system , diabetes mellitus
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.