A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy
Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. The well established role of de novo mutations of sodium channel SCN1A in Dravet Syndrome supports this view, but the etiology of many cases of epileptic encephalopathy remains unknown. We sought to...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114001351 |
| _version_ | 1818870001993515008 |
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| author | Mark Estacion Janelle E. O'Brien Allison Conravey Michael F. Hammer Stephen G. Waxman Sulayman D. Dib-Hajj Miriam H. Meisler |
| author_facet | Mark Estacion Janelle E. O'Brien Allison Conravey Michael F. Hammer Stephen G. Waxman Sulayman D. Dib-Hajj Miriam H. Meisler |
| author_sort | Mark Estacion |
| collection | DOAJ |
| description | Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. The well established role of de novo mutations of sodium channel SCN1A in Dravet Syndrome supports this view, but the etiology of many cases of epileptic encephalopathy remains unknown. We sought to identify the genetic cause in a patient with early onset epileptic encephalopathy by whole exome sequencing of genomic DNA. The heterozygous mutation c. 2003C>T in SCN8A, the gene encoding sodium channel Nav1.6, was detected in the patient but was not present in either parent. The resulting missense substitution, p.Thr767Ile, alters an evolutionarily conserved residue in the first transmembrane segment of channel domain II. The electrophysiological effects of this mutation were assessed in neuronal cells transfected with mutant or wildtype cDNA. The mutation causes enhanced channel activation, with a 10 mV depolarizing shift in voltage dependence of activation as well as increased ramp current. In addition, pyramidal hippocampal neurons expressing the mutant channel exhibit increased spontaneous firing with PDS-like complexes as well as increased frequency of evoked action potentials. The identification of this new gain-of-function mutation of Nav1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Nav1.6, and further expands the role of de novo mutations in severe epilepsy. |
| first_indexed | 2024-12-19T12:00:05Z |
| format | Article |
| id | doaj.art-cb9e6a6bb2564fef8e644044862c49c5 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T12:00:05Z |
| publishDate | 2014-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-cb9e6a6bb2564fef8e644044862c49c52022-12-21T20:22:31ZengElsevierNeurobiology of Disease1095-953X2014-09-0169117123A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathyMark Estacion0Janelle E. O'Brien1Allison Conravey2Michael F. Hammer3Stephen G. Waxman4Sulayman D. Dib-Hajj5Miriam H. Meisler6The Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, CT 06520, USA; The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USADepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USANew Orleans Children's Hospital, New Orleans, LA 70118, USAARL Division of Biotechnology, University of Arizona, Tucson, AZ 85721, USAThe Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, CT 06520, USA; The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USAThe Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, CT 06520, USA; The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Correspondence to: S.D. Dib-Hajj, Neuroscience Research Center (Bldg 34), VA Connecticut (127A), 950 Campbell Ave, West Haven, CT 06516, USA. Fax: +1 203 937 3801.Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA; Correspondence to: M.H. Meisler, Department of Human Genetics, 4909 Buhl, University of Michigan, Ann Arbor, MI 48109-5618, USA. Fax: +1 734 763 9691.Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. The well established role of de novo mutations of sodium channel SCN1A in Dravet Syndrome supports this view, but the etiology of many cases of epileptic encephalopathy remains unknown. We sought to identify the genetic cause in a patient with early onset epileptic encephalopathy by whole exome sequencing of genomic DNA. The heterozygous mutation c. 2003C>T in SCN8A, the gene encoding sodium channel Nav1.6, was detected in the patient but was not present in either parent. The resulting missense substitution, p.Thr767Ile, alters an evolutionarily conserved residue in the first transmembrane segment of channel domain II. The electrophysiological effects of this mutation were assessed in neuronal cells transfected with mutant or wildtype cDNA. The mutation causes enhanced channel activation, with a 10 mV depolarizing shift in voltage dependence of activation as well as increased ramp current. In addition, pyramidal hippocampal neurons expressing the mutant channel exhibit increased spontaneous firing with PDS-like complexes as well as increased frequency of evoked action potentials. The identification of this new gain-of-function mutation of Nav1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Nav1.6, and further expands the role of de novo mutations in severe epilepsy.http://www.sciencedirect.com/science/article/pii/S0969996114001351EpilepsySodium channelDe novo mutationEpileptic encephalopathy |
| spellingShingle | Mark Estacion Janelle E. O'Brien Allison Conravey Michael F. Hammer Stephen G. Waxman Sulayman D. Dib-Hajj Miriam H. Meisler A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy Neurobiology of Disease Epilepsy Sodium channel De novo mutation Epileptic encephalopathy |
| title | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy |
| title_full | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy |
| title_fullStr | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy |
| title_full_unstemmed | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy |
| title_short | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy |
| title_sort | novel de novo mutation of scn8a nav1 6 with enhanced channel activation in a child with epileptic encephalopathy |
| topic | Epilepsy Sodium channel De novo mutation Epileptic encephalopathy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114001351 |
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