@article{c60750feeb504075938d3de9a62d4b0d,
title = "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 alpha-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 beta-subunits (beta 1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na-v. Mutations in beta-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in beta-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 alpha-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the beta 2-subunit. Functional analysis using current-clamp revealed that the beta 2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the beta 2-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.",
keywords = "Diabetic neuropathy, voltage-gated sodium channels, sodium channel beta-subunits, neuropathic pain, FAST INACTIVATION, NA(V)1.8 MUTATION, ALPHA-SUBUNIT, SEGMENT IVS6, DOMAIN IV, EXCITABILITY, ACTIVATION, NEURONS, PREVALENCE, POTENTIALS",
author = "Matthew Alsaloum and Mark Estacion and Rowida Almomani and Gerrits, {Monique M.} and Boenhof, {Gidon J.} and Dan Ziegler and Rayaz Malik and Maryam Ferdousi and Giuseppe Lauria and Merkies, {Ingemar S. J.} and Faber, {Catharina G.} and Sulayman Dib-Hajj and Waxman, {Stephen G.} and {de Greef}, B. and Hoeijmakers, {J. G. J.} and M. Sopacua and Smeets, {H. J. M.} and Vanoevelen, {J. M.} and Eijkenboom and P. Lindsey and R. Almomani and M. Taiana and M. Marchi and R. Lombardi and D. Cazzato and Boneschi, {F. M.} and A. Zauli and F. Clarelli and S. Santoro and A.B. Lopez and A. Quattrini and S. Cestele and O. Chever and M. Tavakoli and R. Malik and D. Kapetis and Xenakis, {M. N.} and M. Mantegazza and F. Battiato and A. Strom and {PROPANE Study Grp}",
note = "Funding Information: The authors would like to acknowledge Peng Zhao and Lawrence Macala for technical assistance. The authors would also like to thank Fadia Dib-Hajj for preparation of DNA constructs. This material is the result of work supported with resources and the use of facilities at the VA Medical Center West Haven. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Propane Study Group: B de Greef (the Netherlands), JGJ Hoeijmakers (the Netherlands), M Sopacua (the Netherlands), HJM Smeets (the Netherlands), JM Vanoevelen (the Netherlands), I Eijkenboom (the Netherlands), P Lindsey (the Netherlands), R Almomani (the Netherlands), M Taiana (Italy), M Marchi (Italy), R Lombardi (Italy), D Cazzato (Italy), FM Boneschi (Italy), A Zauli (Italy), F Clarelli (Italy), S Santoro (Italy), I Lopez, A Quattrini (Italy), S Cest{\`e}le, O Chever, M Tavakoli, R Malik, D Kapetis, MN Xenakis (the Netherlands), M Mantegazza (France), F Battiato (Germany), A Strom (Germany), S Cest{\`e}le (France), O Chever (France), and R Malik (United Kingdom). Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by grant 602273 from the European Union Seventh Framework Programme FP7/2007– 2013 and by grants from the Rehabilitation Research Service, Department of Veterans Affairs. The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. Publisher Copyright: {\textcopyright} The Author(s) 2019.",
year = "2019",
month = may,
doi = "10.1177/1744806919849802",
language = "English",
volume = "15",
pages = "1--14",
journal = "Molecular Pain",
issn = "1744-8069",
publisher = "SAGE Publications Inc.",
}