A gain-of-function sodium channelβ2-subunit mutation in painful diabetic neuropathy

Abstract

Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in a-subunits of voltage-gated sodium channels (Na v s) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Na v s could expand the spectrum of patients with Na v-related peripheral neuropathies. The auxiliary sodium channel b-subunits (b1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na v. Mutations in b-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in b-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel a-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the b2-subunit. Functional analysis using current-clamp revealed that the b2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the b2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Na v 1.7 fast inactivation and reduced use-dependent inhibition of the Na v 1.7 channel.

New Perspective in Diabetic Neuropathy: From the Periphery to the Brain, a Call for Early Detection, and Precision Medicine

“…Moreover, rare voltage-gated sodium channel Nav 1.7 genetic variants have been shown to be associated with small fiber neuropathy and painful-DPN (142,143). With the development of the voltage-gated sodium channel Nav 1.7 research, more mutation sites related to painful-DPN have been found, but the mutation perhaps needs further validation (144). Interestingly, Blesneac et al found 10 out of 111 patients with painful-DPN harbored rare Nav 1.7 variants and these patients reported more severe pain and increased sensitivity to pressure stimuli on QST (145).…”

Evaluation of molecular inversion probe versus TruSeq® custom methods for targeted next-generation sequencing

“…In this study, we developed a MIPs-NGS and TSCA-NGS targeted re-sequencing panels for nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B) known to be associated with neuropathic pain [19,27], and compared their sensitivity, specificity, targeting efficiency, performance and cost effectiveness. The average targeted regions coverage was 97.3% in MIPs-NGS, and 93.9% in TSCA-NGS.…”

State-of-the-art pharmacotherapy for diabetic neuropathy

“…Voltage-gated sodium channels (NaV) present a potential therapeutic target in the treatment of pDPN [127]. Both experimental and clinical studies have suggested that polymorphisms and mutations in a number of pain-related genes are involved in the facilitation or inhibition of nociception [127,128]. The current concept is that modulation of the ion channels expressed by certain genes may modify the neuropathic pain experience and the response to analgesics [127].…”

“…The PROPANE study group suggested that underlying hyperexcitability induced by the β2-subunit mutation (gain of function) of the Nav 1.7 channel may contribute to pDPN [128]. There are currently a number of potential molecules, which modulate this channel, but none have received marketing authorization.…”