A stop codon mutation in SCN9A causes lack of pain sensation

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.

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

“…Loss-of-function mutations in hNa V 1.7 cause a congenital indifference to pain with no other sensory impairments except anosmia (8,22,23), whereas gain-offunction mutations are associated with painful neuropathies (7,24). Ablation of Na V 1.7 in all mouse sensory neurons abolishes mechanical pain, inflammatory pain, and reflex withdrawal responses to heat, without affecting neuropathic pain.…”

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

“…A different set of gain-of-function mutations that impair inactivation of Na V 1.7 and in some cases produce a persistent current (Fertleman et al, 2006;Dib-Hajj et al, 2008;Jarecki et al, 2008) has been linked to a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing (Fertleman et al, 2006). In contrast, loss-of-function mutations of Na v 1.7 have been linked to congenital inability to experience pain (Cox et al, 2006;Ahmad et al, 2007;Goldberg et al, 2007).…”

NovelSCN9AMutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations

“…The link between Na V 1.7 functional change and pathogenesis Previous studies have concluded that pain-insensitive mutations are due to a total loss of Na V 1.7 channel function (Cox et al, 2006(Cox et al, , 2010Ahmad et al, 2007), which, given the fundamental role of Na V 1.7 in regulating electrical activity in sensory neurons, intuitively explains the painless phenotype. Here, however, we present three novel CIP-associated mutations in Na V 1.7 that all retain some functionality.…”