Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy

Holland, Katherine D.; Kearney, Jennifer A.; Glauser, Tracy A.; Buck, Gerri; Keddache, Mehdi; Blankston, John R.; Glaaser, Ian W.; Kass, Robert S.; Meisler, Miriam H.

doi:10.1016/j.neulet.2007.12.064

Cited by 135 publications

(123 citation statements)

References 35 publications

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“…Although it is not known whether Nav1.1 and Nav1.3 channels produce resurgent currents, mutations that slow the rate of inactivation have been identified in these isoforms in patients with epilepsy (28,29), and it is therefore conceivable that resurgent currents could contribute to the pathophysiology of some inherited epilepsies. In our study, we showed that a mutation in the voltage-sensing segment 4 of the fourth domain, as well as mutations in the IFMT inactivation particle, induced enhanced resurgent currents, which suggests that any mutation that slows the rate of open channel fast inactivation might be able to induce resurgent currents.…”

Section: Figurementioning

confidence: 99%

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

et al. 2010

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Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.

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Section: Figurementioning

confidence: 99%

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

et al. 2010

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“…In the current study, we show that a common familial ALS mutant, hSOD1 A4V , shifts the voltage dependence and augments total Na + currents of the Na v channel, Na v 1.3, an isoform that is characteristic of embryonic motor neurons [17], which is documented to have a persistent inward sodium current and has been implicated in human neurological disease [20,21]. Our results suggest that changes in the biophysical properties of voltage-gated sodium channels are important in the genesis of mutant SOD1-induced hyperexcitability in ALS.…”

Section: Introductionmentioning

confidence: 62%

Mutant SOD1 protein increases Nav1.3 channel excitability

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in~20% of familial ALS and 2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Na v 1.3) mediated by heightened total Na + conductance and a hyperpolarizing shift in the voltage dependence of Na v 1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.

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“…24 One mutation, K354Q, has been reported in Nav1.3 in a patient with cryptogenic epilepsy. 25 In addition, Estacion and colleagues demonstrated that K354Q mutation enhanced the Nav1.3 persistent current nearly twofold, and the ramp current more than twofold.…”

Section: Discussionmentioning

confidence: 99%

Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats

Huang

Mao

Lin

et al. 2013

Journal of Neurotrauma

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During the secondary injury period after traumatic brain injury (TBI), depolarization of neurons mediated by voltagegated sodium channels (VGSCs) leads to cellular abnormalities and neurological dysfunction. Alterations in expression of different a subunits of VGSCs can affect early brain pathology following TBI. This study detected the expression of Nav1.3 mRNA and protein in the rat cortex post-TBI. Adult male Sprague-Dawley rats were randomly assigned to sham-TBI, mild-TBI (mTBI), or severe-TBI (sTBI) groups. TBI was induced using a fluid percussion device at magnitudes of 1.5-1.6 atm (mTBI) and 2.9-3.0 atm (sTBI). Nav1.3 mRNA and protein levels in the ipsilateral-injured cortex were examined at 2 h, 12 h, 24 h, and 72 h post-TBI by real-time reverse transcriptase quantitative polymerase chain reaction and Western blot. Brains were collected at 24 h, 72 h, and 7 days post-TBI for TUNEL staining and cell count analysis. Immunofluorescence was performed to localize expression of Nav1.3 protein in the ipsilateral-injured cortex. Expression of Nav1.3 mRNA and protein were significantly upregulated in mTBI and sTBI groups when compared with the sham-TBI group at 2 h and 12 h post-TBI. Nav1.3 mRNA and protein levels in the sTBI group were much higher than in the mTBI group at 12 h post-TBI. TUNEL-positive cell numbers were significantly higher in the sTBI group than in the mTBI at 24 h, 72 h, and 7 days post-TBI. Expression of Nav1.3 was observed predominantly in neurons of the cortex. These findings indicated significant upregulation in the expression of Nav1.3 mRNA and protein in the rat ipsilateral-injured cortex at the very early stage post-TBI, and were also correlated with TBI severity.

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Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy

Cited by 135 publications

References 35 publications

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

Mutant SOD1 protein increases Nav1.3 channel excitability

Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats

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