SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology

Abstract

ObjectiveThe SCN11A gene encodes the NaV1.9 sodium channel found exclusively in peripheral nociceptive neurons.MethodsAll enrolled participants were evaluated clinically by electrophysiologic studies, DNA sequencing, and punch skin biopsies.ResultsAll affected family members are afflicted by episodes of pain. Pain was predominantly nociceptive, but not neuropathic in nature, which led a diagnosis of fibromyalgia in some patients. All patients had normal findings in nerve conduction studies for detecting large nerve fiber neuropathies and skin biopsies for detecting small nerve fiber pathology.ConclusionsUnlike those patients with missense mutations in SCN11A, small fiber sensory neuropathy, and neuropathic pain, the Arg225Cys SCN11A in the present study causes predominantly nociceptive pain with minimal features of neuropathic pain and undetectable pathophysiologic changes of peripheral neuropathy. This finding is consistent with dysfunction of nociceptive neurons. In addition, since nociceptive pain in patients has led to the diagnosis of fibromyalgia, this justifies a future search of mutations of SCN11A in patients with additional pain phenotypes such as fibromyalgia to expand the clinical spectrum beyond painful small fiber sensory neuropathy.

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

“…It is now known that there are nine voltage-gated sodium channel subtypes along with numerous splice variants. Of note, three of these isotypes: Na V 1.7 16,17 , Na V 1.8 [18][19][20] , and Na V 1.9 21,22 have been found to be principally expressed in primary afferent nociceptors. The relevance of these isotypes to human pain has been suggested by the observation that a loss-of-function mutation in Na V 1.7 (SCN9A) leads to congenital insensitivity to pain (CIP), a rare genetic disorder.…”

“…Further, it is not clear that such antibodies can gain access to the appropriate Na V 1.7 channels and yield a reliable block of their function. Consequently, in spite of preclinical studies demonstrating that decreased Na V 1.7 activity leads to a reduction in inflammatory and neuropathic pain [16][17][18][19][20][21][22]37 , no molecule targeting this gene product has reached the final phase of clinical trials 32 . We therefore took an alternative approach by epigenetically modulating the expression of Na V 1.7 using two genome engineering tools, clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR-Cas9) and zinc-finger proteins (ZFP), such that one could engineer highly specific, long-lasting and reversible treatments for pain.…”

Mechanical allodynia triggered by cold exposure in mice with the Scn11a p.R222S mutation: a novel model of drug therapy for neuropathic pain related to NaV1.9

“…Cold exposure may alter other signaling events in the DRG, such as the overall profile of protein kinase, the specific upregulation of Fyn kinase that regulates Na V 1.7 channels in response to repeated cold stress (Kozaki et al 2015;Li et al 2018), or even other posttranslational modifications, including phosphorylation, that can modify the trafficking and functions of Na V channels in neurons (Laedermann et al 2015). As suggested by previous clinical reports, the relationship of SCN11A gene mutations and environmental changes may be involved in painful disorders (Leipold et al 2013;Zhang et al 2013;Huang et al 2014;Han et al 2015;Woods et al 2015;Okuda et al 2016;Han et al 2017;King et al 2017;Castoro et al 2018;Kabata et al 2018;Huang et al 2019). Clearly, further research, for example with stable Na V 1.9-expressing cell lines, is necessary to clarify the molecular mechanisms of SCN11A gain-offunction mutations.…”

“…Although lamotrigine alleviated the pain of patients carrying the SCN11A p.R222H mutation in one study (Han et al 2017 ), it was ineffective against the pain of a patient with the same p.R222H mutation in another study (Tanaka et al 2019 ). Gabapentin, a voltage-gated calcium channel blocker, frequently used for the treatment of neuropathy, failed to control the nociceptive pain of patients with the SCN11A p.R225C mutation (Castoro et al 2018 ). Acetaminophen (AcAP) and cyclooxygenase-2 inhibitors, common analgesic agents, are often prescribed for patients with familial episodic pain syndromes (Okuda et al 2016 ; Kabata et al 2018 ), yet they were also unable to alleviate the pain symptoms.…”

SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub‐phenotypes

“…Using a mouse knockout model, Na V 1.9 was shown to be a key mediator of peripheral pain hypersensitivity (Amaya et al, ). Moreover, several gain‐of‐function mutations in SCN11A have been implicated in familial pain syndrome (Castoro et al, ; Leng et al, ; Zhang et al, ). In addition, certain SCN11A mutations were associated with postoperative pain (Sun et al, ).…”