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DGAT2 Mutation in a Family with Autosomal‐Dominant Early‐Onset Axonal Charcot‐Marie‐Tooth Disease
Author(s) -
Hong Young Bin,
Kang Junghee,
Kim Ji Hyun,
Lee Jinho,
Kwak Geon,
Hyun Young Se,
Nam Soo Hyun,
Hong Hyun Dae,
Choi YuRi,
Jung SungChul,
Koo Heasoo,
Lee Ji Eun,
Choi ByungOk,
Chung Ki Wha
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22959
Subject(s) - biology , missense mutation , exome sequencing , endoplasmic reticulum , ataxia , genetics , zebrafish , mutation , gene , neuroscience
ABSTRACT Charcot‐Marie‐Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal‐dominant axonal CMT with early‐onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O‐acyltransferase 2 ( DGAT2 ) gene. DGAT2 encodes an endoplasmic reticulum‐mitochondrial‐associated membrane protein, acyl‐CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and 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. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal‐dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.