Journal Article

A stop codon mutation in SCN9A causes lack of pain sensation

Sultan Ahmad, Leif Dahllund, Anders B. Eriksson, Dennis Hellgren, Urban Karlsson, Per-Eric Lund, Inge A. Meijer, Luc Meury, Tracy Mills, Adrian Moody, Anne Morinville, John Morten, Dajan O'Donnell, Carina Raynoschek, Hugh Salter, Guy A. Rouleau and Johannes J. Krupp

in Human Molecular Genetics

Volume 16, issue 17, pages 2114-2121
Published in print September 2007 | ISSN: 0964-6906
Published online June 2007 | e-ISSN: 1460-2083 | DOI:
A stop codon mutation in SCN9A causes lack of pain sensation

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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.

Journal Article.  5316 words.  Illustrated.

Subjects: Genetics and Genomics

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