Expression of pathogenic SCN9A mutations in the zebrafish: A model to study small fiber neuropathy

Eijkenboom, I., Sopacua, M., Otten, A.B.C., Gerrits, M.M., Hoeijmakers, J.G.J., Waxman, S.G., Lombardi, R., Lauria, G., Merkies, I.S.J., Smeets, H.J.M., Faber, C.G., Vanoevelen, J.M., PROPANE Study Group
Experimental neurology   311: 257-264 (Journal)
Registered Authors
Nerve density, SCN9A mutations, Small fiber neuropathy, Temperature assay, Zebrafish model
MeSH Terms
  • Animals
  • Disease Models, Animal*
  • Female
  • Gene Expression
  • Humans
  • Male
  • Mutation/genetics*
  • NAV1.7 Voltage-Gated Sodium Channel/biosynthesis*
  • NAV1.7 Voltage-Gated Sodium Channel/genetics*
  • Small Fiber Neuropathy/genetics*
  • Small Fiber Neuropathy/metabolism*
  • Small Fiber Neuropathy/pathology
  • Zebrafish
30316835 Full text @ Exp. Neurol.
Small fiber neuropathy (SFN) patients experience a spectrum of sensory abnormalities, including attenuated responses to non-noxious temperatures in combination with a decreased density of the small-nerve fibers. Gain-of-function mutations in the voltage-gated sodium channels SCN9A, SCN10A and SCN11A have been identified as an underlying genetic cause in a subpopulation of patients with SFN. Based on clinical-diagnostic tests for SFN, we have set up a panel of two read-outs reflecting SFN in zebrafish, being nerve density and behavioral responses. Nerve density was studied using a transgenic line in which the sensory neurons are GFP-labelled. For the behavioral experiments, a temperature-controlled water compartment was developed. This device allowed quantification of the behavioral response to temperature changes. By using these read-outs we demonstrated that zebrafish embryos transiently overexpressing the pathogenic human SCN9A p.(I228M) or p.(G856D) mutations both have a significantly decreased density of the small-nerve fibers. Additionally, larvae overexpressing the p.(I228M) mutation displayed a significant increase in activity induced by temperature change. As these features closely resemble the clinical hallmarks of SFN, our data suggest that transient overexpression of mutant human mRNA provides a model for SFN in zebrafish. This disease model may provide a basis for testing the pathogenicity of novel genetic variants identified in SFN patients. Furthermore, this model could be used for studying SFN pathophysiology in an in vivo model and for testing therapeutic interventions.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes