Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Hawkins, Nicole A.; Kearney, Jennifer A.

doi:10.1111/j.1601-183x.2012.00790.x

Cited by 27 publications

(45 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6,7 Transgenic alteration of Cacna1g expression influenced the Scn2a Q54 phenotype. 7 Other epilepsy modifier genes, including Hlf and Kcnq2 , influence phenotypes in both Scn2a Q54 and Scn1a epilepsy mouse models.…”

Section: Introductionmentioning

confidence: 99%

Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

et al. 2017

View full text Add to dashboard Cite

Summary Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death due to epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/− Dravet phenotype. Scn1a+/− mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/− epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

et al. 2017

View full text Add to dashboard Cite

show abstract

“…We mapped two dominant loci that modify seizure susceptibility of Q54, designated Moe1 (Modifier of Epilepsy) on chromosome 11 and Moe2 on chromosome 19 (Bergren et al, 2005). In contrast to the overall effect, at the Moe1 locus B6 alleles confer increased seizure risk (Hawkins and Kearney, 2012). Fine-mapping and candidate gene analysis by RNA-seq suggested hepatic leukemia factor ( Hlf ) as a candidate modifier at the Moe1 .…”

Section: Introductionmentioning

confidence: 99%

“…Fine-mapping and candidate gene analysis by RNA-seq suggested hepatic leukemia factor ( Hlf ) as a candidate modifier at the Moe1 . B6 mice express lower levels of Hlf transcript compared to SJL (Hawkins and Kearney, 2012), leading us to hypothesize that deletion of Hlf would increase seizure susceptibility.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations

Hawkins

Kearney

2016

Epilepsy Research

View full text Add to dashboard Cite

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 Scn2aQ54 (Q54) mouse model has a strain-dependent epilepsy phenotype. Q54 mice on the C57BL/6J 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 Scn1aKO/+ Dravet syndrome mouse model to examine the effect on premature lethality. Hlf KO/+;Scn1aKO/+ offspring exhibited decreased survival compared to Scn1aKO/+ 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.

show abstract

“…Moe1 (modifier of epilepsy 1) involves multiple genes including Cacna1g, encoding the T-type Ca 2+ channel Ca V 3.1, and Hlf, a PAR bZip transcription factor, whereas Moe2 involves a single gene, Kcnv2, which encodes the silent K + channel subunit K V 8.2 (15)(16)(17). Additionally, RNA sequencing analysis of parent mouse strains revealed several other genes with divergent expression between mouse strains that may contribute to strain-dependent epilepsy severity, including genes directly involved in ion transport and posttranslational regulation of ion channel or transporters (18).…”

mentioning

confidence: 99%

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Thompson

Hawkins

Kearney

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In the Scn2a Q54 mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered Na V 1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features in Scn2a Q54 mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model. Scn2a Q54 mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence in Scn2a Q54 mice with higher activity in F1.Q54 animals. Heterologously expressed Na V 1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability in Scn2a Q54 mice and may represent a therapeutic target for the treatment of epilepsy.epilepsy | voltage-gated sodium channel | CaMKII V oltage-gated sodium channels are essential for the generation and propagation of action potentials in excitable cells (1). These proteins exist as heteromultimeric complexes formed by a large pore-forming α-subunit and one or more auxiliary β-subunits (2). Function of voltage-gated sodium channels is influenced by multiple intracellular factors including protein-protein interactions, channel phosphorylation, and intracellular calcium. The auxiliary β-subunits and a family of FGF homologous factors (FHF) have been shown to modulate trafficking and functional properties of voltage-gated sodium channels (3-5). Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6, 7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8-10). Thus, differences in posttranslational modification of sodium channels may profoundly influence the physiology of excitable cells.Mutations in genes encoding neuronal voltage-gated sodium ch...

show abstract

Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Cited by 27 publications

References 75 publications

Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Contact Info

Product

Resources

About