Human Molecular Genetics Advance Access first published online on June 27, 2007
This version published online on July 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm160
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A stop codon mutation in SCN9A causes lack of pain sensation
1 AstraZeneca R&D Montréal, Department of Molecular Sciences, Ville-St-Laurent, Quebec, Canada 2 AstraZeneca R&D Södertälje, Molecular Pharmacology Department, Södertälje, Sweden 3 AstraZeneca R&D Södertälje, Disease Biology Department, Södertälje, Sweden 4 Ste-Justine Hospital Research Center and The Center for the Study of Brain Diseases; University of Montréal, Montréal, Quebec, Canada 5 AstraZeneca R&D Alderley Park, Research and Development Genetics, Macclesfield, Cheshire, UK
* Correspondence to: Johannes Krupp AstraZeneca R&D, Södertälje, Molecular Pharmacology Department – B209, Forskargatan 20, 15185 Södertälje, Sweden Tel: +46 / (0)8 553 21686, Fax: +46 / (0)8 553 25440 Email: johannes.krupp{at}astrazeneca.com
Received June 1, 2007; Revised June 1, 2007; Accepted June 20, 2007
The general lack of pain experience is a rare occurrence in humans, and the molecular causes for this phenotype are not well understood. Here we have studied a Canadian family from Newfoundland with members that exhibit a congenital inability to experience pain. We have mapped the locus to a 13.7 Mb region on chromosome 2q (2q24.3 – 2q31.1). Screening of candidate genes in this region identified a protein-truncating mutation in SCN9A, which encodes for the voltage-gated sodium channel Nav1.7. The mutation is a C to A transversion at nucleotide 984 transforming the codon for tyrosine 328 to a stop codon. The predicted product lacks all pore-forming regions of Nav1.7. Indeed, expression of this altered gene in a cell line did not produce functional responses, nor did it cause compensatory effects on endogenous voltage-gated sodium currents when expressed in ND7/23 cells. Because a homozygous knock-out of Nav1.7 in mice has been shown to be lethal, we explored why a deficiency of Nav1.7 is non-lethal in humans. Expression studies in monkey, human, mouse and rat tissue indicated species-differences in the Nav1.7 expression profile. Whereas in rodents the channel was strongly expressed in hypothalamic nuclei, only weak mRNA levels were detected in this area in primates. Furthermore, primate pituitary and adrenal glands were devoid of signal whereas these two glands were mRNA-positive in rodents. This species difference may explain the non-lethality of the observed mutation in humans. Our data further establishes Nav1.7 as a critical element of peripheral nociception in humans.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. McGowan, S. B. Hoyt, X. Li, K. A. Lyons, and C. Abbadie A Peripherally Acting Nav1.7 Sodium Channel Blocker Reverses Hyperalgesia and Allodynia on Rat Models of Inflammatory and Neuropathic Pain Anesth. Analg., September 1, 2009; 109(3): 951 - 958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Schmalhofer, J. Calhoun, R. Burrows, T. Bailey, M. G. Kohler, A. B. Weinglass, G. J. Kaczorowski, M. L. Garcia, M. Koltzenburg, and B. T. Priest ProTx-II, a Selective Inhibitor of NaV1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors Mol. Pharmacol., November 1, 2008; 74(5): 1476 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Estacion, S. D. Dib-Hajj, P. J. Benke, R. H. M. te Morsche, E. M. Eastman, L. J. Macala, J. P. H. Drenth, and S. G. Waxman NaV1.7 Gain-of-Function Mutations as a Continuum: A1632E Displays Physiological Changes Associated with Erythromelalgia and Paroxysmal Extreme Pain Disorder Mutations and Produces Symptoms of Both Disorders J. Neurosci., October 22, 2008; 28(43): 11079 - 11088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lampert, A. O. O'Reilly, S. D. Dib-Hajj, L. Tyrrell, B. A. Wallace, and S. G. Waxman A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation J. Biol. Chem., August 29, 2008; 283(35): 24118 - 24127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chatelier, L. Dahllund, A. Eriksson, J. Krupp, and M. Chahine Biophysical Properties of Human Nav1.7 Splice Variants and Their Regulation by Protein Kinase A J Neurophysiol, May 1, 2008; 99(5): 2241 - 2250. [Abstract] [Full Text] [PDF]
|
|