Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.
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.
Greenberg
David A
DA
Division of Statistical Genetics, Department of Psychiatry, and Columbia University Genome Center, Columbia University, 722 West 168th Street, New York, NY 10032, USA. dag2005@columbia.edu
Cayanis
Eftihia
E
Strug
Lisa
L
Marathe
Sudhir
S
Durner
Martina
M
Pal
Deb K
DK
Alvin
Gabriele B
GB
Klotz
Irene
I
Dicker
Elisa
E
Shinnar
Shlomo
S
Bromfield
Edward B
EB
Resor
Stanley
S
Cohen
Jeffrey
J
Moshe
Solomon L
SL
Harden
Cynthia
C
Kang
Harriet
H
D000293:Adolescent; D017668:Age of Onset; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D004829:Epilepsy, Generalized / Q000235:genetics*; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008291:Malate Dehydrogenase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D008291:Malate Dehydrogenase; C495394:malic enzyme 2; human