title: Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development.
abstract: Dominant mutations in voltage-gated sodium channel NaV1.7 cause inherited erythromelalgia, a debilitating pain disorder characterized by severe burning pain and redness of the distal extremities. NaV1.7 is preferentially expressed within peripheral sensory and sympathetic neurons. Here, we describe a novel NaV1.7 mutation in an 11-year-old male with underdevelopment of the limbs, recurrent attacks of burning pain with erythema, and swelling in his feet and hands. Frequency and duration of the episodes gradually increased with age, and relief by cooling became less effective. The patient's sister had short stature and reported similar complaints of erythema and burning pain, but with less intensity. Genetic analysis revealed a novel missense mutation in NaV1.7 (2567G>C; p.Gly856Arg) in both siblings. The G856R mutation, located within the DII/S4-S5 linker of the channel, substitutes a highly conserved non-polar glycine by a positively charged arginine. Voltage-clamp analysis of G856R currents revealed that the mutation hyperpolarized (-11.2 mV) voltage dependence of activation and slowed deactivation but did not affect fast inactivation, compared with wild-type channels. A mutation of Gly-856 to aspartic acid was previously found in a family with limb pain and limb underdevelopment, and its functional assessment showed hyperpolarized activation, depolarized fast inactivation, and increased ramp current. Structural modeling using the Rosetta computational modeling suite provided structural clues to the divergent effects of the substitution of Gly-856 by arginine and aspartic acid. Although the proexcitatory changes in gating properties of G856R contribute to the pathophysiology of inherited erythromelalgia, the link to limb underdevelopment is not well understood.
authors.affiliation: From the Department of Neurology.|the Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510.|the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Tanaka
authors.affiliation: the Department of Physiology and Membrane Biology and.|the Biophysics Graduate Group, University of California, Davis, California 95616.
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Nguyen
authors.affiliation: the Department of Dermatology, Peking University First Hospital, Beijing 100034, China, and.|the Department of Dermatology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China.
authors.forename: Eray Yihui
authors.initials: EY
authors.lastname: Zhou
authors.affiliation: the Department of Dermatology, Peking University First Hospital, Beijing 100034, China, and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: the Department of Physiology and Membrane Biology and.|the Biophysics Graduate Group, University of California, Davis, California 95616.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: From the Department of Neurology.|the Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510.|the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: From the Department of Neurology, stephen.waxman@yale.edu.|the Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510.|the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D002648:Child; D004916:Erythromelalgia / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human
keywords: electrophysiology; erythromelalgia; ion channel; molecular modeling; pain; sodium channel