scholarly journals Identification of a Novel Gain-of-Function Sodium Channel B2 Subunit Mutation in Small Fiber Neuropathy

2020 ◽  
Vol 118 (3) ◽  
pp. 578a-579a
Author(s):  
Matthew Alsaloum ◽  
Peng Zhao ◽  
Monique M. Gerrits ◽  
Rowida Almomani ◽  
Janneke Hoeijmakers ◽  
...  
2020 ◽  
Vol 123 (2) ◽  
pp. 645-657 ◽  
Author(s):  
Seong-il Lee ◽  
Janneke G. J. Hoeijmakers ◽  
Catharina G. Faber ◽  
Ingemar S. J. Merkies ◽  
Giuseppe Lauria ◽  
...  

Gain-of-function variants in voltage-gated sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in 5–10% of patients with idiopathic small fiber neuropathy (I-SFN). Our previous in vitro observations suggest that enhanced sodium channel activity can contribute to a decrease in length of peripheral sensory axons. We have hypothesized that sustained sodium influx due to the expression of SFN-associated sodium channel variants may trigger an energetic deficit in neurons that contributes to degeneration and loss of nerve fibers in SFN. Using an ATP FRET biosensor, we now demonstrate reduced steady-state levels of ATP and markedly faster ATP decay in response to membrane depolarization in cultured DRG neurons expressing an SFN-associated variant NaV1.7, I228M, compared with wild-type neurons. We also observed that I228M neurons show a significant reduction in mitochondrial density and size, indicating dysfunctional mitochondria and a reduced bioenergetic capacity. Finally, we report that exposure to dexpramipexole, a drug that improves mitochondrial energy metabolism, increases the neurite length of I228M-expressing neurons. Our data suggest that expression of gain-of-function variants of NaV1.7 can damage mitochondria and compromise cellular capacity for ATP production. The resulting bioenergetic crisis can consequently contribute to loss of axons in SFN. We suggest that, in addition to interventions that reduce ionic disturbance caused by mutant NaV1.7 channels, an alternative therapeutic strategy might target the bioenergetic burden and mitochondrial damage that occur in SFN associated with NaV1.7 gain-of-function mutations. NEW & NOTEWORTHY Sodium channel NaV1.7 mutations that increase dorsal root ganglion (DRG) neuron excitability have been identified in small fiber neuropathy (SFN). We demonstrate reduced steady-state ATP levels, faster depolarization-evoked ATP decay, and reduced mitochondrial density and size in cultured DRG neurons expressing SFN-associated variant NaV1.7 I228M. Dexpramipexole, which improves mitochondrial energy metabolism, has a protective effect. Because gain-of-function NaV1.7 variants can compromise bioenergetics, therapeutic strategies that target bioenergetic burden and mitochondrial damage merit study in SFN.


Author(s):  
Matthew Alsaloum ◽  
Julie I. R. Labau ◽  
Daniel Sosniak ◽  
Peng Zhao ◽  
Rowida Almomani ◽  
...  

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ 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 the pore-forming voltage-gated sodium channel α subunits (NaVs) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate NaV 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 β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β 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 β2 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 β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.


2011 ◽  
Vol 71 (1) ◽  
pp. 26-39 ◽  
Author(s):  
Catharina G. Faber ◽  
Janneke G. J. Hoeijmakers ◽  
Hye-Sook Ahn ◽  
Xiaoyang Cheng ◽  
Chongyang Han ◽  
...  

2021 ◽  
pp. 135-139
Author(s):  
Leema Reddy Peddareddygari ◽  
Raji P. Grewal

The SCN9A gene encodes a voltage gated sodium channel Nav1.7 in which mutations can result in a wide variety of phenotypes ranging from congenital insensitivity to pain to small fiber neuropathy. We report the genotype phenotype analysis in a family carrying a specific mutation, I1739V, in the SCN9A gene. Neurophysiological studies have documented the gain of function impact of this mutation on this sodium channel. Interestingly, there is significant interfamilial phenotypic variability in individuals carrying this mutation. In our family, a father daughter combination had identical genotypes analyzing the SCN9A gene and multiple other genes known to cause neuropathy. Both of them carry the I1739V mutation but exhibit significant phenotypic variability with complaints of decreased sensitivity to discomfort in the father while the daughter has the clinical and laboratory features consistent with a small fiber neuropathy. We hypothesize that there are modifiers of the I1739V mutation that could involve intronic or exonic gene variants which contribute to this intrafamilial phenotypic variability. Our study has implications for genetic counseling, personalized medicine and the development of drugs to treat neuropathic pain.


2006 ◽  
Vol 37 (5) ◽  
pp. 38
Author(s):  
JANE SALODOF MACNEIL

Sign in / Sign up

Export Citation Format

Share Document