Malic Enzyme 2 May Underlie Susceptibility to Adolescent-Onset Idiopathic Generalized Epilepsy

TY - JOUR

T1 - Malic Enzyme 2 May Underlie Susceptibility to Adolescent-Onset Idiopathic Generalized Epilepsy

AU - Greenberg, David A

AU - Cayanis, Eftihia

AU - Strug, Lisa

AU - Marathe, Sudhir

AU - Durner, Martina

AU - Pal, Deb K

AU - Alvin, Gabriele B

AU - Klotz, Irene

AU - Dicker, Elisa

AU - Shinnar, Shlomo

AU - Bromfield, Edward B

AU - Resor, Stanley

AU - Cohen, Jeffrey

AU - Moshe, Solomon L

AU - Harden, Cynthia

AU - Kang, Harriet

PY - 2005/1

Y1 - 2005/1

N2 - 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 gamma-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.

AB - 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 gamma-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.

KW - Adolescent

KW - Age of Onset

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 18

KW - Epilepsy, Generalized

KW - Genes, Recessive

KW - Genetic Predisposition to Disease

KW - Humans

KW - Lod Score

KW - Malate Dehydrogenase

KW - Polymorphism, Single Nucleotide

U2 - 10.1086/426735

DO - 10.1086/426735

M3 - Article

C2 - 15532013

SN - 0002-9297

VL - 76

SP - 139

EP - 146

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -