TY - JOUR
T1 - A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy
AU - Alsaloum, M.
AU - Labau, J.I.R.
AU - Sosniak, D.
AU - Zhao, P.
AU - Almomani, R.
AU - Gerrits, M.
AU - Hoeijmakers, J.G.J.
AU - Lauria, G.
AU - Faber, C.G.
AU - Waxman, S.G.
AU - Dib-Hajj, S.
N1 - Funding Information:
This work was supported by Award B9253-C from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service (S.G.W., M.A., J.I.R.L., D.S., P.Z., S.D.H). M.A. is supported by the NIH/NIGMS Medical Scientist Training Program T32GM007205 and the Lo Graduate Fellowship for Excellence in Stem Cell Research from the Yale Stem Cell Center. J.I.R.L., G.L., C.G.F., S.G.W., and S.D.H. received funding from the Molecule-to-Man Pain Network, from the European Union's Horizon 2020 research and innovation program under grant agreement No. 721841. R.A., M.G., J.G.J.H., G.L., C.G.F., S.G.W., and S.D.H received funding through the European Union Seventh Framework Programme grant 602273. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University.
Publisher Copyright:
© 2021 American Physiological Society. All rights reserved.
PY - 2021/9/9
Y1 - 2021/9/9
N2 - Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.
AB - Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.
KW - beta 2 subunit
KW - small fiber neuropathy (SFN)
KW - sodium channel beta subunits
KW - tetrodotoxin-sensitive voltage-gated sodium channels
KW - voltage-gated sodium (Nav) channels
KW - VOLTAGE-GATED SODIUM
KW - FEBRILE SEIZURES
KW - PERIPHERAL NEUROPATHY
KW - GENERALIZED EPILEPSY
KW - DIAGNOSTIC-CRITERIA
KW - NA(V)1.8 MUTATION
KW - GENE
KW - INACTIVATION
KW - EXPRESSION
KW - PAIN
U2 - 10.1152/jn.00184.2021
DO - 10.1152/jn.00184.2021
M3 - Article
C2 - 34320850
SN - 0022-3077
VL - 126
SP - 827
EP - 839
JO - Journal of Neurophysiology
JF - Journal of Neurophysiology
IS - 3
ER -