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Identification and characterization of novel genes causing inherited peripheral
neuropathy
Young Bin Hong
Stem Cell & Regenerative Medicine Institute, Samsung Medical Center
Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies
with diverse genetic causes. Recently, we identified two novel genes causing CMT through
whole exome sequencing. One is p.I43N mutation in peripheral myelin protein 2 (PMP2)
gene and the other is p.Y223H mutation in diacylglycerol O-acyltransferase 2 (DGAT2) gene.
Patients with PMP2 mutation exhibited muscle atrophy started in the distal portion of the leg
with the age at onset of the first to second decades. 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. Patients with mutation in
DGAT2 exhibited an autosomal-dominant axonal CMT with early-onset, sensory ataxia,
tremor, and slow disease progression. The overexpression of the mutant DGAT2 significantly
inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human
DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. These
data suggest that mutation of DGAT2 is the novel underlying cause of an autosomaldominant axonal CMT2 neuropathy. Collectively, this study might expand the genetic and
clinical features of CMT and enhance our understanding on inherited peripheral neuropathy.