Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Baker, Mark D.; Nassar, Mohammed A.

doi:10.1007/s00424-020-02419-9

Cited by 32 publications

(36 citation statements)

References 136 publications

(161 reference statements)

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“…Recently, more and more evidence has shown that mutations in the SCN9A gene are closely related to abnormal pain. Among them, paroxysmal severe pain and primary erythematous limb pain are all due to misintentional mutations in certain positions of the human SCN9A gene sequence encoding Nav1.7 protein [ 44 , 45 ]. DRG neuron Nav1.7 has a high expression in the inflammatory pain model of rats 46 ), and the SCN9A gene mutation rat of DRG neuron has significantly reduced responsiveness to inflammatory pain [ 47 48 ].…”

Section: Discussionmentioning

confidence: 99%

Analgesia effect of lentivirus-siSCN9A infected neurons in vincristine induced neuropathic pain rats

Bao-quan

Zhu

2021

Bioengineered

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At present, the mechanism of siSCN9A in Vincristine (VCR)-induced neuropathic pain (NP) is still unclear. This study aimed to explore the analgesic mechanism of lentivirus-siSCN9A (LV-siSCN9A) infected neurons against NP. 40 male Sprague-Dawley (SD) rats were divided into a control group (injected with normal saline), a model group (VCR-induced NP model), a LV-SC group (NP model mice were injected with LV-SC-infected dorsal root ganglia (DRG) neuron cells under the microscope), and a LV-siSCN9A group (NP model mice were injected with LV-siSCN9A-infected DRG neuron cells under the microscope, with 10 rats in each group. The changes of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats in different groups were detected by behavior testing, the Nav1.7 changes in each group were detected by immunofluorescence double standard and Western-blot method. It was found that compared with the control group, the MWT and TWL of the rats in model group were significantly decreased ( P < 0.05), and the expression levels of Nav1.7 messenger ribonucleic acid (mRNA) and proteins were significantly increased ( P < 0.05). Compared with LV-SC group, the MWT and TWL of rats in LV-siSCN9A group were significantly increased ( P < 0.05), the expression levels of Nav1.7 mRNA and proteins were significantly decreased ( P < 0.05), and the CGRP expression of spinal dorsal horn was significantly decreased. It was concluded that the LV-siSCN9A infected neurons could play an analgesic role by down-regulating Nav1.7 expression induced by VCR in NP model.

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Section: Discussionmentioning

confidence: 99%

Analgesia effect of lentivirus-siSCN9A infected neurons in vincristine induced neuropathic pain rats

Bao-quan

Zhu

2021

Bioengineered

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“…Conversely, loss-of-function mutations in SCN9A contribute to CIP (Klein et al, 2013). To date, more than 100 mutations in SCN9A have been reported, but only 42 have been associated with CIP (Baker and Nassar, 2020; Supplementary Table 1 and Figure 2A). Among the SCN9A mutations identified in CIP patients, most were non-sense, frameshift, or splicing mutations, all of which produced non-functional and truncated Nav1.7 proteins; however, we identified a novel homozygous missense mutation (c.4015T > C, p. Cys1339Arg) in SCN9A in a patient with CIP, which abolished the current density and the Nav1.7 function.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain

Xie

Tang

et al. 2021

Front. Neurosci.

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Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous SCN9A mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

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“…The FEPS3 phenotype has been associated with nine heterogeneous mutations in SCN11A , most of which are positively charged residues in the voltage sensor of the transmembrane segment S4 66 . It is believed that these mutations alter the gating properties of the mutant channel and lower the threshold for action potentials.…”

Section: Pathogenic Mechanisms Of Fepsmentioning

confidence: 99%

Familial Episodic Pain Syndromes

Shen¹,

Zheng²,

Hong³

2022

JPR

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Over the past decades, advances in genetic sequencing have opened a new world of discovery of causative genes associated with numerous pain-related syndromes. Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age. According to the phenotypic and genetic properties, FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4, which are caused by mutations in the TRPA1, SCN10A, SCN11A , and SCN9A genes, respectively. Functional studies have revealed that all missense mutations in these genes are closely associated with the gain-of-function of cation channels. Because some FEPS patients may show a relative treatability and favorable prognosis, it is worth paying attention to the diagnosis and management of FEPS as early as possible. In this review, we state the common clinical manifestations, pathogenic mechanisms, and potential therapies of the disease, and provide preliminary opinions about future research for FEPS.

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Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Cited by 32 publications

References 136 publications

Analgesia effect of lentivirus-siSCN9A infected neurons in vincristine induced neuropathic pain rats

Analgesia effect of lentivirus-siSCN9A infected neurons in vincristine induced neuropathic pain rats

Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain

Familial Episodic Pain Syndromes

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