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Gene Review:

GABRA4 - gamma-aminobutyric acid (GABA) A receptor,...

Homo sapiens

Synonyms: GABA(A) receptor subunit alpha-4, Gamma-aminobutyric acid receptor subunit alpha-4

Collins, A.L. et al., Ma, D.Q. et al., Glykys, J. et al., Roberts, D.S. et al., McLean, P.J. et al., et al.

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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

Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptor{alpha}4 Subunits in Hippocampal Neurons. Roberts, D.S., Hu, Y., Lund, I.V., Brooks-Kayal, A.R., Russek, S.J. J. Biol. Chem. (2006) [Pubmed]
A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Glykys, J., Peng, Z., Chandra, D., Homanics, G.E., Houser, C.R., Mody, I. Nat. Neurosci. (2007) [Pubmed]
Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Ma, D.Q., Whitehead, P.L., Menold, M.M., Martin, E.R., Ashley-Koch, A.E., Mei, H., Ritchie, M.D., Delong, G.R., Abramson, R.K., Wright, H.H., Cuccaro, M.L., Hussman, J.P., Gilbert, J.R., Pericak-Vance, M.A. Am. J. Hum. Genet. (2005) [Pubmed]
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. McLean, P.J., Farb, D.H., Russek, S.J. Genomics (1995) [Pubmed]
Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. Roberts, D.S., Raol, Y.H., Bandyopadhyay, S., Lund, I.V., Budreck, E.C., Passini, M.A., Passini, M.J., Wolfe, J.H., Brooks-Kayal, A.R., Russek, S.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Collins, A.L., Ma, D., Whitehead, P.L., Martin, E.R., Wright, H.H., Abramson, R.K., Hussman, J.P., Haines, J.L., Cuccaro, M.L., Gilbert, J.R., Pericak-Vance, M.A. Neurogenetics (2006) [Pubmed]

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