Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases

Yang, Cuiwei; Hua, Yi; Zhang, Weiqin; Xu, Jialu; Xu, Lu; Gao, Feng; Jiang, Peifang

doi:10.1007/s10072-018-3300-y

Cited by 17 publications

(16 citation statements)

References 5 publications

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“…In contrast, the SCN9A gain-of-function mutations cause genetic painful neuropathies such as small fiber neuropathy, primary erythromelalgia and paroxysmal extreme pain disorder ( de Lera Ruiz and Kraus, 2015 ; Vetter et al, 2017 ). The Na V 1.7 expression in the CNS is responsible for anosmia and hyposmia, always linked to painless phenotypes, and epilepsy (presence of different variants in patients showing seizures and Dravet syndrome, and of two SCN9A mutations related to epilepsy phenotype), as well as to autism spectrum disorder ( Dib-Hajj et al, 2013 ; Mulley et al, 2013 ; Rubinstein et al, 2018 ; Yang C. et al, 2018 ). Na V 1.7 has also been reported to be the major Na V subtype in irritating, itchy cough conveyed by DRG neurons ( Muroi and Undem, 2014 ; Sun et al, 2017 ).…”

Section: Voltage-gated Sodium Channels Expressed In Drg Neuronsmentioning

confidence: 99%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

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Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers are officially used to treat moderate to severe, and even mild, pain. However, the consequent strong and not so rare complications that occur, including addiction and overdose, combined with pain management costs, remain an important societal and economic concern. In this context, animal venom toxins represent an original source of antinociceptive peptides that mainly target ion channels (such as ASICs as well as TRP, CaV, KV and NaV channels) involved in pain transmission. The present review aims to highlight the NaV1.7 channel subtype as an antinociceptive target for spider toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these primary sensory neurons, the first ones in contact with pain stimulus and conveying the nociceptive message, (ii) the electrophysiological properties of the different NaV channel subtypes expressed in these neurons, with a particular attention on the NaV1.7 subtype, an antinociceptive target of choice that has been validated by human genetic evidence, and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, that present high affinity for the NaV1.7 subtype associated with evidenced analgesic efficacy in animal models.

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Section: Voltage-gated Sodium Channels Expressed In Drg Neuronsmentioning

confidence: 99%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

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“…The SCN9A gene encodes for the NaV1.7 channel, located in chromosome 2q24 (Yang et al, 2018). NaV1.7 is expressed preferably in the PNS, but it is also expressed in the CNS (Cen et al, 2017).…”

Section: Nav17mentioning

confidence: 99%

“…Being that, after treatment with OXC (120 µmol/L), N641Y and K655R reduced sodium current and decreased the opening time of the channel, while W1150R did not alter that (Zhang S. et al, 2020). However, in a study conducted by Yang et al (2018), one of the patients presented generalized tonic-clonic Faster recovery from inactivation More susceptible to clonic and tonic seizures induced by electrical stimulation (mice) Enhanced persistent current (Singh et al, 2009;Zhang S. et al, 2020) I1901fs C-terminal…”

Section: Nav17mentioning

confidence: 99%

“…Generalized tonic-clonic seizure (Yang et al, 2018) Non genetic origin mutations reported* K655R Focal seizures with secondary generalization High-potential spike activity, paroxysmal release, and d frequency power enhancement (EEG) (Zhang S. et al, 2020) seizure with fever, treated with sodium valproic acid, and a LoF mutation I1901fs was observed (Yang et al, 2018) ( Table 5).…”

Section: Epilepsymentioning

confidence: 99%

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Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

et al. 2020

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Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.

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“…These individuals exhibit congenital insensitivity (CIP) to pain and completely lack thermal and mechanical pain thresholds [20]. In addition to pain insensitivity, Na V 1.7 loss-of-function mutations produce anosmia, a loss of sense of smell [21], and variable cases of epilepsy [22]. The high expression of Na V 1.7 in nociceptive DRGs and phenotypes of human patients with Na V 1.7 mutations underscores the importance of this specific voltage-gated sodium channel subtype in pain and has led many researchers to study Na V 1.7 in pain models.…”

Section: Na V 17 -An Introduction To the "Gatekeeper" Of Painmentioning

confidence: 99%

Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

Chew

Bellampalli

Dustrude

et al. 2019

Biochemical Pharmacology

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The peripherally expressed voltage-gated sodium Na V 1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na V 1.7 has been the focus of intense investigation but, to date, no Na V 1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na V 1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na V 1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na V 1.7 therapeutics is currently unknown. The demonstration that loss of Na V 1.7 function is associated with upregulation of endogenous opioids and potentiation of mu-and delta-opioid receptor activities, suggests that targeting only Na V 1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial and disputed. Thus, additional new targetsregulators, modulators-are needed. In this context, we mine the literature for the known interactome of Na V 1.7 with a focus on protein interactors that affect the channel's trafficking or

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Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases

Cited by 17 publications

References 5 publications

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

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