Open AccessTFG mutation induces haploinsufficiency and drives axonal Charcot–Marie–Tooth disease by causing neurite degeneration
Author(s) -
Chen Xihui,
Liu Fangfang,
Chen Kun,
Wang Yufeng,
Yin Anan,
Kang Xiaowei,
Yang Shanming,
Zhao Hanwen,
Dong Songqi,
Li Yunqing,
Chen Jing,
Wu Yuanming
Publication year - 2022
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13943
Subject(s) - haploinsufficiency , neurite , zebrafish , mutation , neurodegeneration , biology , atrophy , microbiology and biotechnology , neuroscience , degeneration (medical) , phenotype , disease , pathology , genetics , medicine , in vitro , gene
Aims TFG ‐related axonal Charcot–Marie–Tooth (CMT) disease is a late‐onset, autosomal dominant, hereditary motor, and sensory neuropathy characterized by slowly progressive weakness and atrophy of the distal muscles. The objective of this study was to determine the common pathogenic mechanism of TFG ‐related CMT type 2 (CMT2) caused by different mutations and establish a direct association between TFG haploinsufficiency and neurodegeneration. Methods Three individuals carrying the TFG p.G269V mutation but with varying disease durations were studied. The effect of the p.G269V mutation was confirmed by analyzing protein samples extracted from the blood of two individuals. The functional consequences of both CMT2 mutant gene products were evaluated in vitro. The effect of TFG deficiency in the nervous system was examined using zebrafish models and cultured mouse neurons. Results Overexpression of p.G269V TFG failed to enhance soluble TFG levels by generating insoluble TFG aggregates. TFG deficiency disrupted neurite outgrowth and induced neuronal apoptosis both in vivo and in vitro and further impaired locomotor capacity in zebrafish, which was consistent with the phenotype in patients. Wnt signaling was activated as a protective factor in response to TFG deficiency. Conclusion CMT2‐related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.