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

Ivo Eijkenboom, Maurice Sopacua, Auke Otten, Monique Gerrits, Janneke Hoeijmakers, Stephen G. Waxman, Raffaella Lombardi, Giuseppe Lauria, I.S.J. Merkies, Hubertus J.M. Smeets, Karin Faber, Jo Vanoevelen, PROPANE Study Grp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)257-264
Number of pages8
JournalExperimental Neurology
Volume311
DOIs
Publication statusPublished - Jan 2019

Keywords

  • Small-fiber neuropathy
  • SCN9A mutations
  • Zebrafish model
  • Nerve density
  • Temperature assay
  • DIAGNOSTIC-CRITERIA
  • SODIUM-CHANNELS
  • IN-VIVO
  • DEGENERATION
  • NEURONS
  • PAIN
  • ACTIVATION
  • NAV1.7
  • GENES
  • SKIN

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