Abstract
Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a Q54 has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a Q54 mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J × SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a Q54 epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a Q54 mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 359-366 |
| Number of pages | 8 |
| Journal | Mammalian Genome |
| Volume | 20 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2009 |
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ASJC Scopus subject areas
- Genetics
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Fine mapping of an epilepsy modifier gene on mouse Chromosome 19. / Bergren, Sarah K.; Rutter, Elizabeth D.; Kearney, Jennifer A.
In: Mammalian Genome, Vol. 20, No. 6, 01.06.2009, p. 359-366.Research output: Contribution to journal › Article
TY - JOUR
T1 - Fine mapping of an epilepsy modifier gene on mouse Chromosome 19
AU - Bergren, Sarah K.
AU - Rutter, Elizabeth D.
AU - Kearney, Jennifer A.
PY - 2009/6/1
Y1 - 2009/6/1
N2 - Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a Q54 has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a Q54 mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J × SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a Q54 epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a Q54 mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.
AB - Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a Q54 has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a Q54 mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J × SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a Q54 epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a Q54 mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.
UR - http://www.scopus.com/inward/record.url?scp=67651183610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651183610&partnerID=8YFLogxK
U2 - 10.1007/s00335-009-9193-6
DO - 10.1007/s00335-009-9193-6
M3 - Article
C2 - 19513789
AN - SCOPUS:67651183610
VL - 20
SP - 359
EP - 366
JO - Mammalian Genome
JF - Mammalian Genome
SN - 0938-8990
IS - 6
ER -