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 language | English |
|---|---|
| Pages (from-to) | 257-264 |
| Number of pages | 8 |
| Journal | Experimental Neurology |
| Volume | 311 |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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Keywords
- Nerve density
- SCN9A mutations
- Small-fiber neuropathy
- Temperature assay
- Zebrafish model
ASJC Scopus subject areas
- Neurology
- Developmental Neuroscience
Cite this
Expression of pathogenic SCN9A mutations in the zebrafish : A model to study small-fiber neuropathy. / on behalf of the PROPANE Study Group.
In: Experimental Neurology, Vol. 311, 01.01.2019, p. 257-264.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Expression of pathogenic SCN9A mutations in the zebrafish
T2 - A model to study small-fiber neuropathy
AU - on behalf of the PROPANE Study Group
AU - Eijkenboom, Ivo
AU - Sopacua, Maurice
AU - Otten, Auke B.C.
AU - Gerrits, Monique M.
AU - Hoeijmakers, Janneke G.J.
AU - Waxman, Stephen G.
AU - Lombardi, Raffaella
AU - Lauria, Giuseppe
AU - Merkies, Ingemar S.J.
AU - Smeets, Hubert J.M.
AU - Faber, Catharina G.
AU - Vanoevelen, Jo M.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Nerve density
KW - SCN9A mutations
KW - Small-fiber neuropathy
KW - Temperature assay
KW - Zebrafish model
UR - http://www.scopus.com/inward/record.url?scp=85055679768&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055679768&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2018.10.008
DO - 10.1016/j.expneurol.2018.10.008
M3 - Article
VL - 311
SP - 257
EP - 264
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
ER -