Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy

David A. Greenberg, Eftihia Cayanis, Lisa Strug, Sudhir Marathe, Martina Durner, Deb K. Pal, Gabriele B. Alvin, Irene Klotz, Elisa Dicker, Shlomo Shinnar, Edward B. Bromfield, Stanley Resor, Jeffrey Cohen, Solomon L. Moshe, Cynthia Harden, Harriet Kang

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter γ-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.

Original languageEnglish (US)
Pages (from-to)139-146
Number of pages8
JournalAmerican Journal of Human Genetics
Volume76
Issue number1
DOIs
StatePublished - Jan 2005

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Enzymes
gamma-Aminobutyric Acid
Single Nucleotide Polymorphism
Aminobutyrates
Chromosomes, Human, Pair 18
Mitochondrial Genome
Pyruvic Acid
Haplotypes
Genes
Neurotransmitter Agents
Idiopathic Generalized Epilepsy
Epilepsy
Seizures
Odds Ratio
Genotype
Confidence Intervals
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Greenberg, D. A., Cayanis, E., Strug, L., Marathe, S., Durner, M., Pal, D. K., ... Kang, H. (2005). Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. American Journal of Human Genetics, 76(1), 139-146. https://doi.org/10.1086/426735

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. / Greenberg, David A.; Cayanis, Eftihia; Strug, Lisa; Marathe, Sudhir; Durner, Martina; Pal, Deb K.; Alvin, Gabriele B.; Klotz, Irene; Dicker, Elisa; Shinnar, Shlomo; Bromfield, Edward B.; Resor, Stanley; Cohen, Jeffrey; Moshe, Solomon L.; Harden, Cynthia; Kang, Harriet.

In: American Journal of Human Genetics, Vol. 76, No. 1, 01.2005, p. 139-146.

Research output: Contribution to journalArticle

Greenberg, DA, Cayanis, E, Strug, L, Marathe, S, Durner, M, Pal, DK, Alvin, GB, Klotz, I, Dicker, E, Shinnar, S, Bromfield, EB, Resor, S, Cohen, J, Moshe, SL, Harden, C & Kang, H 2005, 'Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy', American Journal of Human Genetics, vol. 76, no. 1, pp. 139-146. https://doi.org/10.1086/426735
Greenberg, David A. ; Cayanis, Eftihia ; Strug, Lisa ; Marathe, Sudhir ; Durner, Martina ; Pal, Deb K. ; Alvin, Gabriele B. ; Klotz, Irene ; Dicker, Elisa ; Shinnar, Shlomo ; Bromfield, Edward B. ; Resor, Stanley ; Cohen, Jeffrey ; Moshe, Solomon L. ; Harden, Cynthia ; Kang, Harriet. / Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. In: American Journal of Human Genetics. 2005 ; Vol. 76, No. 1. pp. 139-146.
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