title: Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes.
abstract: SCN9A, the gene which encodes voltage-gated sodium channel Na(v)1.7, is located on human chromosome 2 within a cluster of other members of this gene family. Na(v)1.7 is present at high levels in most peripheral nociceptive neurons in dorsal root ganglion (DRG) and in sympathetic neurons. In addition to its focal tissue-specific expression, Na(v)1.7 is distinguished by its ability to amplify small depolarizations, thus acting as a threshold channel and modulating excitability. Dominantly inherited gain-of-function mutations in SCN9A have been linked to two familial painful disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). One set of mutations leads to severe episodes of pain in the feet and hands in patients with IEM, and a different set of mutations causes pain in a perirectal, periocular, and mandibular distribution in patients with PEPD. These mutations allow mutant channels to activate in response to weaker stimuli, or to remain open longer in response to stimulation. The introduction of mutant channels into DRG neurons alters electrogenesis and renders these primary sensory neurons hyperexcitable. Mutant Na(v)1.7 channels lower the threshold for single action potentials and increase the number of action potentials that neurons fire in response to suprathreshold stimuli. In contrast, recessively inherited loss-of-function mutations in SCN9A, which cause a loss of function of Na(v)1.7 in patients, lead to indifference to pain with sparing of motor and cognitive abilities. The central role of Na(v)1.7 in these disorders, and the apparently limited consequences of loss of this channel in humans make it an attractive target for treatment of pain.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D004916:Erythromelalgia / Q000150:complications; D006801:Humans; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels