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

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2004 Nov 9

PMID 15532013

Citations 25

Authors

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

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Genetic heterogeneity in familial forms of genetic generalized epilepsy: from mono- to oligogenism.

Dahawi M, de Sainte Agathe J, Elmagzoub M, Ahmed E, Buratti J, Courtin T Hum Genomics. 2024; 18(1):130.

PMID: 39574152 PMC: 11583555. DOI: 10.1186/s40246-024-00659-9.

Upregulation of ACSL, ND75, Vha26 and sesB genes by antiepileptic drugs resulted in genotoxicity in drosophila.

Shamapari R, Nagaraj K Toxicol Res (Camb). 2024; 13(6):tfae180.

PMID: 39507589 PMC: 11535366. DOI: 10.1093/toxres/tfae180.

Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right-to-left shunt-induced hypoxia.

Dong B, Lu Y, He S, Li B, Li Y, Lai Q MedComm (2020). 2023; 4(4):e334.

PMID: 37576864 PMC: 10422075. DOI: 10.1002/mco2.334.

Suppression of the human malic enzyme 2 modifies energy metabolism and inhibits cellular respiration.

Hsieh J, Chen K, Wang C, Liu G, Ye J, Chou Y Commun Biol. 2023; 6(1):548.

PMID: 37217557 PMC: 10202922. DOI: 10.1038/s42003-023-04930-y.

Investigation of Maternal Effects, Maternal-Fetal Interactions, and Parent-of-Origin Effects (Imprinting) for Candidate Genes Positioned on Chromosome 18q21, in Probands with Schizophrenia and their First-Degree Relatives.

Lee K, Lee B, Park J, Lee Y, Moon E, Jeong H Psychiatry Investig. 2019; 16(6):450-458.

PMID: 31247704 PMC: 6603700. DOI: 10.30773/pi.2019.04.12.

References

Kananura C, Haug K, Sander T, Runge U, Gu W, Hallmann K . A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002; 59(7):1137-41. DOI: 10.1001/archneur.59.7.1137. View

Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M . Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002; 31(2):184-9. DOI: 10.1038/ng885. View

Pal D, Evgrafov O, Tabares P, Zhang F, Durner M, Greenberg D . BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003; 73(2):261-70. PMC: 1180366. DOI: 10.1086/377006. View

Kanno T, Kanno Y, Siegel R, Jang M, Lenardo M, Ozato K . Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell. 2004; 13(1):33-43. DOI: 10.1016/s1097-2765(03)00482-9. View

Greenberg D, Durner M, Keddache M, Shinnar S, Resor S, Moshe S . Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet. 2000; 66(2):508-16. PMC: 1288104. DOI: 10.1086/302763. View

Hassel B, Brathe A . Neuronal pyruvate carboxylation supports formation of transmitter glutamate. J Neurosci. 2000; 20(4):1342-7. PMC: 6772368. View

Meldrum B . Pharmacology of GABA. Clin Neuropharmacol. 1982; 5(3):293-316. DOI: 10.1097/00002826-198205030-00004. View

McKenna M, Stevenson J, Huang X, Tildon J, Zielke C, Hopkins I . Mitochondrial malic enzyme activity is much higher in mitochondria from cortical synaptic terminals compared with mitochondria from primary cultures of cortical neurons or cerebellar granule cells. Neurochem Int. 2000; 36(4-5):451-9. DOI: 10.1016/s0197-0186(99)00148-5. View

Escayg A, MacDonald B, Meisler M, Baulac S, Huberfeld G, An-Gourfinkel I . Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet. 2000; 24(4):343-5. DOI: 10.1038/74159. View

10.

Abecasis G, Cookson W . GOLD--graphical overview of linkage disequilibrium. Bioinformatics. 2000; 16(2):182-3. DOI: 10.1093/bioinformatics/16.2.182. View

11.

Clayton D, Jones H . Transmission/disequilibrium tests for extended marker haplotypes. Am J Hum Genet. 1999; 65(4):1161-9. PMC: 1288249. DOI: 10.1086/302566. View

12.

Durner M, Keddache M, Tomasini L, Shinnar S, Resor S, Cohen J . Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol. 2001; 49(3):328-35. View

13.

Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prudhomme J . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet. 2001; 28(1):46-8. DOI: 10.1038/ng0501-46. View

14.

Hassel B . Pyruvate carboxylation in neurons. J Neurosci Res. 2001; 66(5):755-62. DOI: 10.1002/jnr.10044. View

15.

Greenberg D, Delgado-Escueta A, Maldonado H, Widelitz H . Segregation analysis of juvenile myoclonic epilepsy. Genet Epidemiol. 1988; 5(2):81-94. DOI: 10.1002/gepi.1370050204. View

16.

Greenberg D, Delgado-Escueta A, Widelitz H, Sparkes R, Treiman L, Maldonado H . Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Med Genet. 1988; 31(1):185-92. DOI: 10.1002/ajmg.1320310125. View

17.

. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989; 30(4):389-99. DOI: 10.1111/j.1528-1157.1989.tb05316.x. View

18.

Weissbecker K, Durner M, Janz D, Scaramelli A, Sparkes R, Spence M . Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. Am J Med Genet. 1991; 38(1):32-6. DOI: 10.1002/ajmg.1320380109. View

19.

Durner M, Sander T, Greenberg D, Johnson K, Janz D . Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology. 1991; 41(10):1651-5. DOI: 10.1212/wnl.41.10.1651. View

20.

Greenberg D, Durner M, Delgado-Escueta A . Evidence for multiple gene loci in the expression of the common generalized epilepsies. Neurology. 1992; 42(4 Suppl 5):56-62. View