Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development

Tanaka, Brian S.; Nguyen, Phuong T.; Zhou, Eray Yihui; Yong, Yang; Yarov‐Yarovoy, Vladimir; Dib‐Hajj, Sulayman D.; Waxman, Stephen G.

doi:10.1074/jbc.m117.778779

Cited by 19 publications

(12 citation statements)

References 57 publications

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“…Over 20 different IEM variants have been discovered in Na v 1.7, and almost all variants investigated so far result in a hyperpolarizing shift of activation, allowing Na v 1.7 to open at lower potentials compared with the wild type, [174][175][176][177][178][179][180][181][182][183][184][185][186][187] in familial cases, 175,[188][189][190] and children. 178,191 This left shift of activation enhances excitability, intuitively explaining the pain phenotype. 177,192,193 The phenotype, however, can be complex and variable, 188,[194][195][196][197][198][199] even within families carrying the same variant.…”

Section: Voltage-gated Sodium Channelopathies In Sfnmentioning

confidence: 98%

“…Gain‐of‐function variants that shift activation of Na v 1.7 in a hyperpolarizing direction, slow deactivation, and enhance ramp currents cause IEM. Over 20 different IEM variants have been discovered in Na v 1.7, and almost all variants investigated so far result in a hyperpolarizing shift of activation, allowing Na v 1.7 to open at lower potentials compared with the wild type, in familial cases, and children . This left shift of activation enhances excitability, intuitively explaining the pain phenotype .…”

Section: Epidemiologymentioning

confidence: 99%

“…Most SFN variants in Na V 1.7 are associated with distal pain, but the G856D variant was linked to a more complex phenotype of very severe pain, together with erythema, dysautonomia, and small hands and small feet (acromesomelia) . The IEM‐associated G856R variant was recently also shown to be associated with impaired distal limb development, suggesting that some gain‐of‐function variants of Na V 1.7 may adversely affect limb morphogenesis during development . Furthermore, some variants present with severe autonomic symptoms, while others do not.…”

Section: Epidemiologymentioning

confidence: 99%

“…suggesting that some gain-of-function variants of Na V 1.7 may adversely affect limb morphogenesis during development. 191 2.10.6 | Na V 1.9 in SFN Na V 1.9 is preferentially expressed in small-diameter DRG neurons, trigeminal ganglion neurons, and intrinsic myenteric neurons. 246 Several human pain disorders have been linked to dominant gain-of-function Na V 1.9 variants, including early-onset pain in distal extremities, [247][248][249] cold-aggravated pain, 250 and SFN.…”

Section: Na V 17 In Channelopathy-associated Insensitivity To Painmentioning

confidence: 99%

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Small‐fiber neuropathy: Expanding the clinical pain universe

Sopacua

Hoeijmakers

Merkies

et al. 2019

J Peripheral Nervous Sys

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Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Nav1.7, Nav1.8 and Nav1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

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Section: Voltage-gated Sodium Channelopathies In Sfnmentioning

confidence: 98%

Section: Epidemiologymentioning

confidence: 99%

Section: Epidemiologymentioning

confidence: 99%

Section: Na V 17 In Channelopathy-associated Insensitivity To Painmentioning

confidence: 99%

See 2 more Smart Citations

Small‐fiber neuropathy: Expanding the clinical pain universe

Sopacua

Hoeijmakers

Merkies

et al. 2019

J Peripheral Nervous Sys

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“…Genetic research has identified a link between cases of inherited EM and mutations in the Nav1.7 sodium channel encoded by the SCN9A gene 17,18. Nav1.7 subtypes are preferentially expressed in sensory and sympathetic ganglia neurons, and mutations result in neuronal excitability by reducing current threshold and enhancing repetitive firing in dorsal root ganglia 19,20. These mutations have rarely been detected in sporadic or secondary cases.…”

Section: Introductionmentioning

confidence: 99%

Current pain management strategies for patients with erythromelalgia: a critical review

Tham¹,

Giles²

2018

JPR

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Erythromelalgia (EM) is a rare disorder characterized by erythematous, warm, painful extremities, which is often precipitated by cold conditions. The pathophysiology of EM is incompletely understood. Recent investigations have identified sodium channelopathy as a genetic cause for this pain condition, classified as primary inherited EM. Other subtypes are idiopathic EM and secondary EM. The management of pain in EM is challenging as no single therapy has been found to be effective. There is varying response to pharmacotherapy and significant variability within this clinical population, resulting in a stepwise trial and error approach. Consequently, EM is often associated with poorer health-related quality of life with higher morbidity. There is currently no consensus or guidelines on management of pain in EM. This is a review of the literature on management of pain using pharmacologic, procedural intervention and nonpharmacologic treatment in children and adults with EM.

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Ion Channels as Therapeutic Drug Targets

García¹,

Kaczorowski²

2021

Burger's Medicinal Chemistry and Drug Discovery

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Ion channels comprise a large and diverse family of proteins that control many physiological functions. For this reason, a number of inherited diseases result from mutations in specific genes that alter the functions of given ion channels. Drugs used to treat a variety of pathophysiological conditions derive their benefits from interacting with specific ion channel(s), and efforts to develop novel ion channel drugs that would address unmet clinical needs are ongoing in pharmaceutical, biotech, and academic institutions. During the past period of time, major developments in functional screening technologies have afforded the study of these proteins in high‐density formats. In addition, a large body of information concerning the structure of different ion channels has become available. In some cases, intimate details of the interactions between drugs and ion channels have been obtained, which may help with designing more potent and selective ion channel modulators. Although a number of ion channel modulators have entered clinical development, lack of therapeutic efficacy or toxicity issues have caused termination of the development of many of these agents. Nonetheless, with all accumulated experience and new technological advancements, expectations are high for the successful development of novel ion channel modulators in the future.

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Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development

Cited by 19 publications

References 57 publications

Small‐fiber neuropathy: Expanding the clinical pain universe

Small‐fiber neuropathy: Expanding the clinical pain universe

Current pain management strategies for patients with erythromelalgia: a critical review

Ion Channels as Therapeutic Drug Targets

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