Title: A stop codon mutation in SCN9A causes lack of pain sensation.

Authors: 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, Johannes J Krupp

Journal, date & volume: Hum. Mol. Genet., 2007 Sep 1 , 16, 2114-21

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17597096

Abstract
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 Na(v)1.7. 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 Na(v)1.7. 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 Na(v)1.7 in mice has been shown to be lethal, we explored why a deficiency of Na(v)1.7 is non-lethal in humans. Expression studies in monkey, human, mouse and rat tissue indicated species-differences in the Na(v)1.7 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 Na(v)1.7 as a critical element of peripheral nociception in humans.