Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome
Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ∼20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic phenot...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1149391/full |
| _version_ | 1827955235842162688 |
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| author | Anat Mavashov Anat Mavashov Marina Brusel Marina Brusel Jiaxing Liu Victoria Woytowicz Haneui Bae Ying-Hsin Chen Vardhan S. Dani Elena Cardenal-Muñoz Vittoria Spinosa José Ángel Aibar Moran Rubinstein Moran Rubinstein Moran Rubinstein |
| author_facet | Anat Mavashov Anat Mavashov Marina Brusel Marina Brusel Jiaxing Liu Victoria Woytowicz Haneui Bae Ying-Hsin Chen Vardhan S. Dani Elena Cardenal-Muñoz Vittoria Spinosa José Ángel Aibar Moran Rubinstein Moran Rubinstein Moran Rubinstein |
| author_sort | Anat Mavashov |
| collection | DOAJ |
| description | Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ∼20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic phenotypes of a novel preclinical Dravet mouse model harboring the R613X nonsense Scn1a mutation. Scn1aWT/R613X mice, on a mixed C57BL/6J:129S1/SvImJ background, exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, modeling some non-epileptic Dravet-associated phenotypes. Conversely, Scn1aWT/R613X mice, on the pure 129S1/SvImJ background, had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice (pure 129S1/SvImJ background) died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and NaV1.1 protein levels to ∼50% in heterozygous Scn1aWT/R613X mice (on either genetic background), with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet. |
| first_indexed | 2024-04-09T14:42:36Z |
| format | Article |
| id | doaj.art-a514e71d032547999588604f107d69b1 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-09T14:42:36Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-a514e71d032547999588604f107d69b12023-05-03T05:27:10ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-05-011710.3389/fncel.2023.11493911149391Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndromeAnat Mavashov0Anat Mavashov1Marina Brusel2Marina Brusel3Jiaxing Liu4Victoria Woytowicz5Haneui Bae6Ying-Hsin Chen7Vardhan S. Dani8Elena Cardenal-Muñoz9Vittoria Spinosa10José Ángel Aibar11Moran Rubinstein12Moran Rubinstein13Moran Rubinstein14Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, IsraelGoldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelGoldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelTevard Biosciences, Cambridge, MA, United StatesTevard Biosciences, Cambridge, MA, United StatesTevard Biosciences, Cambridge, MA, United StatesTevard Biosciences, Cambridge, MA, United StatesTevard Biosciences, Cambridge, MA, United StatesDravet Syndrome Foundation Spain, Madrid, SpainDravet Syndrome Foundation Spain, Madrid, SpainDravet Syndrome Foundation Spain, Madrid, SpainSagol School of Neuroscience, Tel Aviv University, Tel Aviv, IsraelGoldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ∼20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic phenotypes of a novel preclinical Dravet mouse model harboring the R613X nonsense Scn1a mutation. Scn1aWT/R613X mice, on a mixed C57BL/6J:129S1/SvImJ background, exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, modeling some non-epileptic Dravet-associated phenotypes. Conversely, Scn1aWT/R613X mice, on the pure 129S1/SvImJ background, had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice (pure 129S1/SvImJ background) died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and NaV1.1 protein levels to ∼50% in heterozygous Scn1aWT/R613X mice (on either genetic background), with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet.https://www.frontiersin.org/articles/10.3389/fncel.2023.1149391/fullDravet syndromemouse modelseizureshyperactivityopen access |
| spellingShingle | Anat Mavashov Anat Mavashov Marina Brusel Marina Brusel Jiaxing Liu Victoria Woytowicz Haneui Bae Ying-Hsin Chen Vardhan S. Dani Elena Cardenal-Muñoz Vittoria Spinosa José Ángel Aibar Moran Rubinstein Moran Rubinstein Moran Rubinstein Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome Frontiers in Cellular Neuroscience Dravet syndrome mouse model seizures hyperactivity open access |
| title | Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome |
| title_full | Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome |
| title_fullStr | Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome |
| title_full_unstemmed | Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome |
| title_short | Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome |
| title_sort | heat induced seizures premature mortality and hyperactivity in a novel scn1a nonsense model for dravet syndrome |
| topic | Dravet syndrome mouse model seizures hyperactivity open access |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1149391/full |
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