Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development
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Le résumé fourni par la source
Dominant mutations in voltage-gated sodium channel Na V 1.7 cause inherited erythromelalgia, a debilitating pain disorder characterized by severe burning pain and redness of the distal extremities. Na V 1.7 is preferentially expressed within peripheral sensory and sympathetic neurons. Here, we describe a novel Na V 1.7 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 Na V 1.7 (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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development
- Date Crossref
- 01/06/2017
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Yale University the Center for Neuroscience & Regeneration Research pays non établi dans la noticeUniversité ou école supérieure
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VA Connecticut Healthcare System pays non établi dans la noticeÉtablissement de santé
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Membrane Technology & Research (United States) pays non établi dans la noticeEntreprise
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University of California the Biophysics Graduate Group pays non établi dans la noticeUniversité ou école supérieure
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Peking University the Department of Dermatology pays non établi dans la noticeUniversité ou école supérieure
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Peking University First Hospital pays non établi dans la noticeÉtablissement de santé
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Beijing Tsinghua Chang Gung Hospital pays non établi dans la noticeÉtablissement de santé
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Tsinghua University Beijing Tsinghua Changgung Hospital pays non établi dans la noticeUniversité ou école supérieure
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From the Department of Neurology pays non établi dans la noticeInstitution
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the Rehabilitation Research Center pays non établi dans la noticeStructure de recherche
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the Department of Physiology and Membrane Biology and pays non établi dans la noticeInstitution
the Center for Neuroscience & Regeneration Research — Yale University, VA Connecticut Healthcare System et Membrane Technology & Research (United States), avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.