Candidate gene analysis of the human metabotropic glutamate receptor type 4 (GRM4) in patients with juvenile myoclonic epilepsy.
Hereditary factors play a major role in the genetically complex etiology of juvenile myoclonic epilepsy (JME). Linkage studies in families of JME probands suggest a susceptibility locus (EJM1) for idiopathic generalized epilepsy (IGE) in the chromosomal region 6p21.3 near the HLA region. The gene encoding the metabotropic glutamate receptor type 4 (GRM4) has been localized within the EJM1-region and represents a high-ranking candidate gene. Therefore, we have sequenced the coding regions and regulatory GRM4 sequences in 20 IGE probands who were derived from families of JME probands providing positive linkage evidence to the HLA-DQ locus. Our mutation analysis detected three synonymous exonic single nucleotide polymorphisms (SNP; exon-7: c.1455T > C, exon-8: c.2002A > G, exon-10: c.2733C > T), one SNP in the 3'-untranslated region (c.2890A > G), and two intronic SNPs (intron-3: IVS3 + 2732A > G, intron-7: IVS7 + 39C > T). None of the identified SNPs was likely to affect receptor function or gene expression. The population-based association study did not show significant differences in the allele and genotype frequencies of the common c.1455T > C SNP between 144 German JME probands and 144 healthy population controls (P > 0.84). Likewise, the family-based transmission disequilibrium test did not indicate a preferential transmission of exon-7 SNP alleles in 31 informative parent-child transmissions (P = 0.86). Our results provide no evidence that genetic variation of the GRM4 gene confers susceptibility to JME-related IGE syndromes.
Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnologies, Brescia University Medical School, Brescia, Italy.
Claudia
C
Izzi
Alessandro
A
Barbon
Mohammad Reza
MR
Toliat
Armin
A
Heils
Christian
C
Becker
Peter
P
Nürnberg
Thomas
T
Sander
Sergio
S
Barlati
D000293:Adolescent; D000328:Adult; D002648:Child; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*
D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4