Diabetes mellitus (DM) is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy (DPN) is one of the most common. A substantial number of patients with DPN develop chronic pain, but the genetic and epigenetic factors that predispose DPN patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in α-subunits of voltage-gated sodium channels (Navs) in patients with painful DPN. Mutations in proteins that regulate trafficking or functional properties of Navs could expand the spectrum of patients with Nav-related peripheral neuropathies. The auxiliary sodium channel β-subunits (β1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Nav. Mutations in β-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in β-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful DPN and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel α-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the β2 subunit. Functional analysis using current-clamp revealed that the β2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the β2 subunit mutation, as evidenced by voltage clamp analysis, we found a depolarizing shift in the voltage-dependence of Nav1.7 fast-inactivation and reduced use-dependent inhibition of the Nav1.7 channel.
A gain-of-function sodium channel beta 2-subunit mutation in painful diabetic neuropathy / M. Alsaloum, M. Estacion, R. Almomani, M. Gerrits, G. Bönhof, D. Ziegler, R. Malik, M. Ferdousi, G. Lauria, I. Merkies, C. Faber, S. Dib-Hajj, S. Waxman. - In: MOLECULAR PAIN. - ISSN 1744-8069. - 15(2019), pp. 1744806919849802.1-1744806919849802.14.
|Titolo:||A gain-of-function sodium channel beta 2-subunit mutation in painful diabetic neuropathy|
|Parole Chiave:||Diabetic neuropathy; voltage-gated sodium channels; sodium channel beta-subunits; neuropathic pain|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1177/1744806919849802|
|Appare nelle tipologie:||01 - Articolo su periodico|