Abstract:
:Mutations in voltage-gated sodium channel genes cause several types of human epilepsies. Often, individuals with the same sodium channel mutation exhibit diverse phenotypes. This suggests that factors beyond the primary mutation influence disease severity, including genetic modifiers. Mouse epilepsy models with voltage-gated sodium channel mutations exhibit strain-dependent phenotype variability, supporting a contribution of genetic modifiers in epilepsy. The Scn2a(Q54) (Q54) mouse model has a strain-dependent epilepsy phenotype. Q54 mice on the C57BL/6J (B6) strain exhibit delayed seizure onset and improved survival compared to [B6xSJL/J]F1.Q54 mice. We previously mapped two dominant modifier loci that influence Q54 seizure susceptibility and identified Hlf (hepatic leukemia factor) as a candidate modifier gene at one locus. Hlf and other PAR bZIP transcription factors had previously been associated with spontaneous seizures in mice thought to be caused by down-regulation of the pyridoxine pathway. An Hlf targeted knockout mouse model was used to evaluate the effect of Hlf deletion on Q54 phenotype severity. Hlf(KO/KO);Q54 double mutant mice exhibited elevated frequency and reduced survival compared to Q54 controls. To determine if direct modulation of the pyridoxine pathway could alter the Q54 phenotype, mice were maintained on a pyridoxine-deficient diet for 6 weeks. Dietary pyridoxine deficiency resulted in elevated seizure frequency and decreased survival in Q54 mice compared to control diet. To determine if Hlf could modify other epilepsies, Hlf(KO/+) mice were crossed with the Scn1a(KO/+) Dravet syndrome mouse model to examine the effect on premature lethality. Hlf(KO/+);Scn1a(KO/+) offspring exhibited decreased survival compared to Scn1a(KO/+) controls. Together these results demonstrate that Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations and that modulation of the pyridoxine pathway can also influence phenotype severity.
journal_name
Epilepsy Resjournal_title
Epilepsy researchauthors
Hawkins NA,Kearney JAdoi
10.1016/j.eplepsyres.2015.11.016subject
Has Abstractpub_date
2016-01-01 00:00:00pages
20-3eissn
0920-1211issn
1872-6844pii
S0920-1211(15)30076-0journal_volume
119pub_type
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journal_title:Epilepsy research
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journal_title:Epilepsy research
pub_type: 临床试验,杂志文章
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journal_title:Epilepsy research
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2005.08.005
更新日期:2005-08-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2009.08.001
更新日期:2009-12-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.08.016
更新日期:2014-11-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
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更新日期:2004-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2010.03.007
更新日期:2010-06-01 00:00:00
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更新日期:2019-11-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2020.106362
更新日期:2020-08-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2008.11.001
更新日期:2009-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章,评审
doi:10.1016/j.eplepsyres.2011.04.017
更新日期:2012-07-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2008.11.004
更新日期:2009-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 临床试验,杂志文章,多中心研究
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更新日期:1996-11-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2013.11.024
更新日期:2014-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2011.10.028
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2020-03-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章,多中心研究
doi:10.1016/j.eplepsyres.2008.10.004
更新日期:2009-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/s0920-1211(03)00029-9
更新日期:2003-03-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/s0920-1211(98)00051-5
更新日期:1998-09-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(88)90016-2
更新日期:1988-07-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2008.11.006
更新日期:2009-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章,评审
doi:10.1016/s0920-1211(99)00046-7
更新日期:1999-09-01 00:00:00
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journal_title:Epilepsy research
pub_type:
doi:10.1016/s0920-1211(98)00108-9
更新日期:1999-03-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2012.07.001
更新日期:2013-02-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2016.02.012
更新日期:2016-05-01 00:00:00