C.H. and A.M.R contributed equally to this study.
Sporadic onset of erythermalgia: A gain-of-function mutation in Nav1.7
Article first published online: 3 JAN 2006
Copyright © 2005 American Neurological Association
Annals of Neurology
Volume 59, Issue 3, pages 553–558, March 2006
How to Cite
Han, C., Rush, A. M., Dib-Hajj, S. D., Li, S., Xu, Z., Wang, Y., Tyrrell, L., Wang, X., Yang, Y. and Waxman, S. G. (2006), Sporadic onset of erythermalgia: A gain-of-function mutation in Nav1.7. Ann Neurol., 59: 553–558. doi: 10.1002/ana.20776
- Issue published online: 17 FEB 2006
- Article first published online: 3 JAN 2006
- Manuscript Accepted: 4 NOV 2005
- Manuscript Revised: 27 OCT 2005
- Manuscript Received: 27 SEP 2005
- Medical Research Service
- Rehabilitation Research Service
- Department of Veterans Affairs
- National Multiple Sclerosis Society
- Erythromelalgia Association
- National High Technology Research and Development Programme of China. Grant Number: 2002BA711A07
- National Natural Science Foundation. Grant Number: 30400168
- The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America and the United Spinal Association with Yale University
Inherited erythermalgia (erythromelalgia) is an autosomal dominant disorder in which patients experience severe burning pain in the extremities, in response to mild thermal stimuli and exercise. Although mutations in sodium channel Nav1.7 have been shown to underlie erythermalgia in several multigeneration families with the disease that have been investigated to date, the molecular basis of erythermalgia in sporadic cases is enigmatic. We investigated the role of Nav1.7 in a sporadic case of erythermalgia in a Chinese family.
Genomic DNA from patients and their asymptomatic family members were sequenced to identify mutations in Nav1.7. Whole-cell patch clamp analysis was used to characterize biophysical properties of wild-type and mutant Nav1.7 channels in mammalian cells.
A single amino acid substitution in the DIIS4-S5 linker of Nav1.7 was present in two children whose parents were asymptomatic. The asymptomatic father was genetically mosaic for the mutation. This mutation produces a hyperpolarizing shift in channel activation and an increase in amplitude of the response to slow, small depolarizations.
Founder mutations in Nav1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia. Ann Neurol 2006