HEREDITARY DEFECTS IN HUMAN SODIUM CHANNELS

Summary

Principal Investigator: Alfred L George
Abstract: DESCRIPTION (provided by applicant): Voltage-gated sodium (NaV) channels are heteromultimeric integral membrane proteins that are responsible for the initial phase of the action potential in most excitable cells. A variety of inherited disorders affecting skeletal muscle contraction (hyperkalemic periodic paralysis, paramyotonia congenita, K+-aggravated myotonia), cardiac excitability (congenital long QT syndrome, idiopathic ventricular fibrillation, familial conduction system disease) and certain forms of epilepsy have been associated with mutations in human NaV channel genes. This proposal is a competing renewal of R01-NS32387 that for 17 years has funded our efforts to elucidate the molecular genetic, pathophysiologic and pharmacologic mechanisms of human sodium "channelopathies". We propose to continue our highly successful research program with a focus on epilepsies associated with mutant brain NaV channels. In Specific Aim 1, we will elucidate the functional consequences of novel epilepsy-associated SCN1A (encoding NaV1.1) mutations with a focus on two unstudied mechanistic aspects of mutant channel dysfunction. First, we will investigate the functional consequences of a subset of mutations within a region of the NaV1.1 C-terminus having conserved Ca2+/calmodulin regulatory elements to test the hypothesis that these alleles affect channel function by altering the response of the channel to internal Ca2+ signaling. Second, we will investigate whether alternative splicing influences the functional consequences of SCN1A mutations associated with divergent clinical phenotypes. In Specific Aim 2, we will elucidate the neurophysiological basis for strain- dependent epilepsy severity using two mechanistically distinct mouse models of epilepsy caused by mutant NaV channels: 1) transgenic mice expressing a gain-of-function Scn2a mutation (Q54 mice);and 2) heterozygous Scn1a knock out (Scn1a+/-) mice, a model of human Dravet syndrome. Both models exhibit strong strain-dependence of epilepsy severity and impaired survival. Strain-dependence of murine phenotypes mimics the variable penetrance and disease expression characteristic of human monogenic epilepsies including those caused by mutant NaV channels. Ongoing efforts to map genomic loci responsible for this phenomenon have identified a new candidate gene for seizure susceptibility using Q54 mice. By integrating existing and future genomic data on modifiers of epilepsy with information about the neurophysiological correlates of phenotype strain-dependence, we expect to generate important new insights into mechanisms responsible for the influence of genetic modifiers relevant to human idiopathic epilepsy, and to identify molecular pathways that could be therapeutic targets. PUBLIC HEALTH RELEVANCE: Epilepsy is a common neurological disorder affecting nearly 1% of the U.S. population. Understanding how genetic factors contribute to the pathogenesis of epilepsy has great importance for diagnosis and treatment of this condition. This grant funds studies of epilepsies caused by genetic mutations in sodium channels, a type of protein important for generating electrical impulses in the brain.
Funding Period: 1994-01-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Single-channel properties of human NaV1.1 and mechanism of channel dysfunction in SCN1A-associated epilepsy
    Carlos G Vanoye
    Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    J Gen Physiol 127:1-14. 2006
  2. pmc Recent genetic discoveries implicating ion channels in human cardiovascular diseases
    Alfred L George
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA Electronic address
    Curr Opin Pharmacol 15:47-52. 2014
  3. pmc Novel SCN3A variants associated with focal epilepsy in children
    Carlos G Vanoye
    Department of Medicine, Vanderbilt University, Nashville, TN, USA
    Neurobiol Dis 62:313-22. 2014
  4. pmc Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling
    Carlos G Vanoye
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    J Gen Physiol 141:193-202. 2013
  5. pmc Leaky channels make weak muscles
    Alfred L George
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 122:4333-6. 2012
  6. pmc Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression
    Christopher H Thompson
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Biol Chem 287:42001-8. 2012
  7. pmc Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome
    Linda Volkers
    Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
    Eur J Neurosci 34:1268-75. 2011
  8. pmc SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs
    Christopher H Thompson
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 0275, USA
    Epilepsia 52:1000-9. 2011
  9. pmc Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility
    Benjamin S Jorge
    Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN 37232 0275, USA
    Proc Natl Acad Sci U S A 108:5443-8. 2011
  10. pmc Ranolazine selectively blocks persistent current evoked by epilepsy-associated Naν1.1 mutations
    Kristopher M Kahlig
    Department of Pharmacology, Vanderbilt University, Nashville, TN 37232 0275, USA
    Br J Pharmacol 161:1414-26. 2010

Detail Information

Publications18

  1. pmc Single-channel properties of human NaV1.1 and mechanism of channel dysfunction in SCN1A-associated epilepsy
    Carlos G Vanoye
    Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    J Gen Physiol 127:1-14. 2006
    ....
  2. pmc Recent genetic discoveries implicating ion channels in human cardiovascular diseases
    Alfred L George
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA Electronic address
    Curr Opin Pharmacol 15:47-52. 2014
    ..These recent discoveries further emphasize the importance of ion channels in the pathophysiology of human disease and as important druggable targets. ..
  3. pmc Novel SCN3A variants associated with focal epilepsy in children
    Carlos G Vanoye
    Department of Medicine, Vanderbilt University, Nashville, TN, USA
    Neurobiol Dis 62:313-22. 2014
    ..Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy. ..
  4. pmc Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling
    Carlos G Vanoye
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    J Gen Physiol 141:193-202. 2013
    ..9 potentiation by G-protein signaling during inflammation and provide a cellular platform useful for the discovery of Na(V)1.9 modulators with potential utility in treating inflammatory pain...
  5. pmc Leaky channels make weak muscles
    Alfred L George
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 122:4333-6. 2012
    ..Their work advances understanding of molecular and cellular mechanisms underlying an inherited channelopathy...
  6. pmc Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression
    Christopher H Thompson
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Biol Chem 287:42001-8. 2012
    ..However, rescue of dysfunctional Na(V)1.1 channels to the plasma membrane could contribute to exacerbating rather than ameliorating the disease...
  7. pmc Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome
    Linda Volkers
    Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
    Eur J Neurosci 34:1268-75. 2011
    ..1 gating. Interestingly, while loss of Na(v) 1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects...
  8. pmc SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs
    Christopher H Thompson
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 0275, USA
    Epilepsia 52:1000-9. 2011
    ..1 transcripts correlated with lower required doses of phenytoin in epileptics. We tested the hypothesis that SCN1A alternative splicing affects the pharmacology of Na(V) 1.1 channels...
  9. pmc Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility
    Benjamin S Jorge
    Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN 37232 0275, USA
    Proc Natl Acad Sci U S A 108:5443-8. 2011
    ..1/Kv8.2 heterotetrameric potassium channels. Our results demonstrate that altered potassium subunit function influences epilepsy susceptibility and implicate Kcnv2 as an epilepsy gene...
  10. pmc Ranolazine selectively blocks persistent current evoked by epilepsy-associated Naν1.1 mutations
    Kristopher M Kahlig
    Department of Pharmacology, Vanderbilt University, Nashville, TN 37232 0275, USA
    Br J Pharmacol 161:1414-26. 2010
    ..Here, we investigated the ability of ranolazine to preferentially inhibit increased persistent current evoked by mutant Na(V) 1.1 channels...
  11. pmc Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide
    J F Desaphy
    Department of Pharmacobiology, University of Bari, Bari, Italy
    Br J Pharmacol 160:1521-33. 2010
    ..We examined the mechanisms by which it is able to block open channels, because these properties may be especially useful to reduce hyperexcitability in pathologies characterized by abnormal sodium channel opening...
  12. pmc Multiplexed transposon-mediated stable gene transfer in human cells
    Kristopher M Kahlig
    Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA
    Proc Natl Acad Sci U S A 107:1343-8. 2010
    ....
  13. pmc Novel SCN1A frameshift mutation with absence of truncated Nav1.1 protein in severe myoclonic epilepsy of infancy
    Erin J McArdle
    Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
    Am J Med Genet A 146:2421-3. 2008
  14. ncbi Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia
    Thao P Nguyen
    Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
    Circ Res 102:364-71. 2008
    ....
  15. ncbi Cardiac sodium channel dysfunction in sudden infant death syndrome
    Dao W Wang
    Departments of Pharmacology, Vanderbilt University, Nashville, Tenn, USA
    Circulation 115:368-76. 2007
    ..We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts...
  16. ncbi Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation
    Kristopher M Kahlig
    Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 0275, USA
    J Neurosci 26:10958-66. 2006
    ....
  17. ncbi Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy
    Iori Ohmori
    Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 0275, USA
    Epilepsia 47:1636-42. 2006
    ..Here we report the functional characterization of eight SCN1A mutations (G177E, I227S, R393H, Y426N, H939Q, C959R, delF1289, and T1909I) previously identified in SMEI probands...
  18. pmc Antiepileptic activity of preferential inhibitors of persistent sodium current
    Lyndsey L Anderson
    Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, U S A
    Epilepsia 55:1274-83. 2014
    ..We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity...

Research Grants30

  1. MECHANISMS OF RESISTANCE TO EXCITOTOXIC CELL DEATH
    PAULA E SCHAUWECKER; Fiscal Year: 2013
    ..Identification of epilepsy modifier genes will provide insight into the pathogenesis of epilepsy and aid in the development of novel therapeutic targets for the treatment of human epilepsy. ..
  2. Physiological mechanisms responsible for cognitive impairments in Dravet Syndrome
    Pierre Pascal Lenck-Santini; Fiscal Year: 2013
    ..It would suggest that additional treatment strategies focusing on cognitive function, other than traditional antiepileptic drugs may be necessary to recover normal cognitive function in affected children. ..
  3. Combined Approach to Genetic Modifiers of Inherited Epilepsy
    Jennifer A Kearney; Fiscal Year: 2013
    ..This will contribute to understanding the basis of epilepsy with more complex inheritance and suggest novel therapeutic targets for the improved treatment of human patients ..
  4. Mechanism and function of Kv channel targeting
    Chen Gu; Fiscal Year: 2013
    ..Therefore, our project to understand how Kv channels are localized to regulate functions of nerve cells will contribute to generate novel strategies for treating diseases of the nervous systems. ..
  5. Identification of Epilepsy Modifier Genes in a Mouse Model
    Nicole A Hawkins; Fiscal Year: 2013
    ..This research has the potential to advance molecular diagnostic capabilities and identify novel therapeutic targets for the improved treatment of human patients. ..
  6. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  7. Structural studies of NaV1.5 and functional implications
    Geoffrey S Pitt; Fiscal Year: 2013
    ....
  8. Brain regions contributing to seizures as a function of age and body temperature
    John C Oakley; Fiscal Year: 2013
    ..Oakley will develop skills required to become an independent investigator using a mouse model of SMEI to understand what brain regions are critically involved in seizures as a function of age and body temperature. ..
  9. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  11. The Genetics and Cell Biology of the Epileptic Mouse Mutant Fitful
    Rebecca M Boumil; Fiscal Year: 2013
    ....
  12. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..