PUBLICATION

TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration

Authors
Chen, X., Liu, F., Chen, K., Wang, Y., Yin, A., Kang, X., Yang, S., Zhao, H., Dong, S., Li, Y., Chen, J., Wu, Y.
ID
ZDB-PUB-220824-1
Date
2022
Source
CNS neuroscience & therapeutics   28(12): 2076-2089 (Journal)
Registered Authors
Keywords
axonal Charcot-Marie-Tooth, haploinsufficiency, neurite degeneration, tropomyosin-receptor kinase-fused gene, zebrafish model
MeSH Terms
  • Humans
  • Phenotype
  • Zebrafish/genetics
  • Animals
  • Mice
  • Charcot-Marie-Tooth Disease*/genetics
  • Charcot-Marie-Tooth Disease*/pathology
  • Haploinsufficiency
  • Mutation
  • Neurites/metabolism
  • Pedigree
(all 11)
PubMed
35986567 Full text @ CNS Neurosci Ther
Abstract
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.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
WT + MO1-tfgcontrolProtruding-mouth
1 - 10 of 54
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ml2TgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    Charcot-Marie-Tooth disease type 2TAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    Target Reagent Reagent Type
    tfgMO1-tfgMRPHLNO
    tfgMO2-tfgMRPHLNO
    1 - 2 of 2
    Show
    Fish
    Fish
    ml2Tg
    ml2Tg + MO1-tfg
    ml2Tg + MO2-tfg
    WT
    WT + MO1-tfg
    WT + MO2-tfg
    1 - 6 of 6
    Show
    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-tfgpolyclonal
      		IgGRabbit
      Ab3-mycmonoclonal
        		IgG2aMouse
        Ab5-map2monoclonal
          		IgG1Mouse
          1 - 3 of 3
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          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          GFPEFGGFP
          1 - 1 of 1
          Show
          Mapping
          No data available
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          Citation
          Chen, X., Liu, F., Chen, K., Wang, Y., Yin, A., Kang, X., Yang, S., Zhao, H., Dong, S., Li, Y., Chen, J., Wu, Y. (2022) TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration. CNS neuroscience & therapeutics. 28(12):2076-2089.