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Acta Physiologica 2013; Volume 207, Supplement 694
92nd Annual Meeting of the German Physiological Society
3/2/2013-3/5/2013
Heidelberg, Germany
ELECTROPHYSIOLOGICAL CHARACTERIZATION OF A LOSS-OF-FUNCTION MUTATION OF NAV1.8 IN A PATIENT WITH ERYTHROMELALGIA
Abstract number: P096
Kist
1
*A.
, Rush A.M., Sagafos
4
D., Namer
1
B., Neacsu
1
C., Eberhardt
1
E., Schmidt
5
R., Lunden
4
L.K., Orstavik
4
K., Zhang
2
Z., Carr
6
T.H., Salter H., Krupp J., Malinowsky
2
D., Wollberg
2
P., Kleggetveit
4
I.P., Schmelz
10
M., Jorum
4
E.,
Lampert
1
A.
1
FAU Erlangen-Nürnberg, Inst. Physiology and Pathophysiology, Erlangen, Germany
2
AstraZeneca, R&D, Södertälje, Sweden
3
Xention Ltd, Cambridge, United Kingdom
4
Oslo University Hospital-Rikshospitalet, Dept. Neurology, Oslo, Norway
5
The University Hospital, Uppsala, Sweden
6
AstraZeneca, R&D, Macclesfield, United Kingdom
7
AstraZeneca Translational Science Centre, Science for Life Laboratory, Solna, Sweden
8
Karolinska Institutet, Dept Clinical Neuroscience, Stockholm, Sweden
9
Ipsen Innovation, Les ulis, France
10
Heidelberg University, Dept. Anesthesiology Mannheim, Mannheim, Germany
Erythromelalgia has been linked to gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel Nav1.7. Mutations in the TTX resistant channels Nav1.8 and Nav1.9 were until recently not known to be connected with inherited pain. Here, we describe a patient with defined symptoms of erythromelalgia carrying the M650K mutation in Nav1.8. To assess the clinical phenotype, microneurography and quantitative sensory testing (QST) was used. The biophysical effects of the mutation were investigated using patch-clamp recordings from transfected sensory neurons (DRGs) and neuroblastoma cells using current- and voltage-clamp methods.
Peripheral nerve recordings showed an increased activity dependent slowing (ADS) and a smaller amount of spontaneous firing compared to a control group of erythromelalgia patients without mutations in their sodium channels. In voltage-clamp recordings, the M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials but did not significantly alter any other tested gating behavior. Current-clamp studies showed that the action potential half-width was significantly broader, and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT.
Enhanced steady-state fast inactivation of M650K Nav1.8 is likely to underlie the reduced firing rate observed in mutant transfected DRGs and may possibly also explain enhanced ADS recorded from the patient's fibers. This study provides evidence that behavior of Nav1.8 can be related to the clinical phenotype of a pain condition.
To cite this abstract, please use the following information:
Acta Physiologica 2013; Volume 207, Supplement 694 :P096