Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes
Abstract Background Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spe...
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BMC
2019-02-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-019-0073-6 |
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doaj-fbf502b38d494e16bcea44feee0b6afb2020-11-25T01:38:38ZengBMCMolecular Medicine1076-15511528-36582019-02-0125111510.1186/s10020-019-0073-6Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypesAnaïs Begemann0Mario A. Acuña1Markus Zweier2Marie Vincent3Katharina Steindl4Ruxandra Bachmann-Gagescu5Annette Hackenberg6Lucia Abela7Barbara Plecko8Judith Kroell-Seger9Alessandra Baumer10Kazuhiro Yamakawa11Yushi Inoue12Reza Asadollahi13Heinrich Sticht14Hanns Ulrich Zeilhofer15Anita Rauch16Institute of Medical Genetics, University of Zurichradiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of ZurichInstitute of Medical Genetics, University of ZurichService de génétique médicale, CHU NantesInstitute of Medical Genetics, University of ZurichInstitute of Medical Genetics, University of ZurichDivision of Child Neurology, University Children’s Hospital Zurichradiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurichradiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of ZurichChildren’s department, Swiss Epilepsy Centre, Clinic LenggInstitute of Medical Genetics, University of ZurichLaboratory for Neurogenetics, RIKEN Center for Brain ScienceNational Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological DisordersInstitute of Medical Genetics, University of ZurichInstitute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of ZurichInstitute of Medical Genetics, University of ZurichAbstract Background Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. Methods To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. Results The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. Conclusions Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.http://link.springer.com/article/10.1186/s10020-019-0073-6SCN2ANav1.2ChannelopathyPatch-clampEpilepsyEpileptic encephalopathy |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Anaïs Begemann Mario A. Acuña Markus Zweier Marie Vincent Katharina Steindl Ruxandra Bachmann-Gagescu Annette Hackenberg Lucia Abela Barbara Plecko Judith Kroell-Seger Alessandra Baumer Kazuhiro Yamakawa Yushi Inoue Reza Asadollahi Heinrich Sticht Hanns Ulrich Zeilhofer Anita Rauch |
| spellingShingle |
Anaïs Begemann Mario A. Acuña Markus Zweier Marie Vincent Katharina Steindl Ruxandra Bachmann-Gagescu Annette Hackenberg Lucia Abela Barbara Plecko Judith Kroell-Seger Alessandra Baumer Kazuhiro Yamakawa Yushi Inoue Reza Asadollahi Heinrich Sticht Hanns Ulrich Zeilhofer Anita Rauch Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes Molecular Medicine SCN2A Nav1.2 Channelopathy Patch-clamp Epilepsy Epileptic encephalopathy |
| author_facet |
Anaïs Begemann Mario A. Acuña Markus Zweier Marie Vincent Katharina Steindl Ruxandra Bachmann-Gagescu Annette Hackenberg Lucia Abela Barbara Plecko Judith Kroell-Seger Alessandra Baumer Kazuhiro Yamakawa Yushi Inoue Reza Asadollahi Heinrich Sticht Hanns Ulrich Zeilhofer Anita Rauch |
| author_sort |
Anaïs Begemann |
| title |
Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes |
| title_short |
Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes |
| title_full |
Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes |
| title_fullStr |
Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes |
| title_full_unstemmed |
Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes |
| title_sort |
further corroboration of distinct functional features in scn2a variants causing intellectual disability or epileptic phenotypes |
| publisher |
BMC |
| series |
Molecular Medicine |
| issn |
1076-1551 1528-3658 |
| publishDate |
2019-02-01 |
| description |
Abstract Background Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. Methods To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. Results The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. Conclusions Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants. |
| topic |
SCN2A Nav1.2 Channelopathy Patch-clamp Epilepsy Epileptic encephalopathy |
| url |
http://link.springer.com/article/10.1186/s10020-019-0073-6 |
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