Disease relevance of GABRA4

• Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant alpha4 subunit gene (GABRA4) expression after status epilepticus [1].

High impact information on GABRA4

• We also ruled out any compensatory upregulation of alpha6 subunits that might have accounted for the ethanol effect in Gabra4(-/-) mice [2].
• Ethanol potentiates the tonic inhibition mediated by such native alpha1/delta GABA(A)Rs in wild-type and in alpha4 subunit-deficient (Gabra4(-/-)) mice, but not in delta subunit-deficient (Gabrd(-/-)) mice [2].
• EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1 [3].
• The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2) [3].
• Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04) [3].

Biological context of GABRA4

• Mapping of the alpha 4 subunit gene (GABRA4) to human chromosome 4 defines an alpha 2-alpha 4-beta 1-gamma 1 gene cluster: further evidence that modern GABAA receptor gene clusters are derived from an ancestral cluster [4].
• Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression [5].
• Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253) [6].
• These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype [6].
• Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients [6].

References