Human Molecular Genetics Advance Access originally published online on June 27, 2007
Human Molecular Genetics 2007 16(17):2114-2121; doi:10.1093/hmg/ddm160
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A stop codon mutation in SCN9A causes lack of pain sensation
1 Department of Molecular Sciences, AstraZeneca R&D Montréal, Ville-St-Laurent, Quebec, Canada, 2 Department of Molecular Pharmacology and 3 Department of Disease Biology, AstraZeneca R&D Södertälje, Södertälje, Sweden, 4 Ste-Justine Hospital Research Center and 5 The Center for the Study of Brain Diseases, University of Montréal, Montréal, Quebec, Canada and 6 Research and Development Genetics, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK
* To whom correspondence should be addressed at: Department of Molecular Pharmacology—B209, AstraZeneca R&D Södertälje, Forskargatan 20, 15185 Södertälje, Sweden. Tel: +46 855321686; Fax: +46 855325440; 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 who 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–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 knockout 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 establish Nav1.7 as a critical element of peripheral nociception in humans.
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