Disease relevance of GABRB3

• Chromosomal rearrangement breakpoints--in one Angelman syndrome (AS) patient with an unbalanced translocation and in another patient with a submicroscopic deletion--are located within the large GABRB3 intron [1].
• In order to determine the genomic organization of the GABAA receptor beta 3 subunit gene (GABRB3) and alpha 5 subunit gene (GABRA5) in chromosome 15q11-q13, we have constructed a high-resolution physical map using the combined techniques of field-inversion gel electrophoresis and phage genomic library screening [1].
• Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate [2].
• A 570-kb contig encompassing GABRB3 and GABRA5 has been constructed in P1, lambda phage, and PAC clones [3].
• The gamma-aminobutyric acid (GABAA) receptor beta 3 (GABRB3) and alpha 5 (GABRA5) subunit genes have been localized to the Angelman and Prader-Willi syndrome region of chromosome 15q11-q13 [4].

Psychiatry related information on GABRB3

• Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014) [5].
• In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity [6].

High impact information on GABRB3

• Uniparental disomy or hemizygous deletion of chromosome 15 results in altered allele-specific replication kinetics compared with normals, suggesting that allele-specific replication within the GABRB3/A5 region may be regulated by reciprocal imprints on the maternal and paternal chromosomes [7].
• Domain organization of allele-specific replication within the GABRB3 gene cluster requires a biparental 15q11-13 contribution [7].
• Evidence of linkage was obtained with a parametric two-point linkage analysis (maximum LOD score of 5.56 at a recombination fraction of 0.001 for marker GABRB3) and was supported by multipoint analysis (maximum LOD score of 6.54 between markers D15S113 and D15S1019) [8].
• The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder [5].
• In both cases, high-resolution banding of the long arm was normal, and FISH of probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of this material [9].

Biological context of GABRB3

• The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome [10].
• The genes encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits beta 3 (GABRB3), alpha 5 (GABRA5), and gamma 3 (GABRG3) map to chromosome 15q11-q13 [3].
• GABRB3 spans 250 kb of DNA and is organized into 9 exons that range from 68 to 504 bp, while GABRA5 is encoded by 11 exons (65 to 924 bp in length) within 86 kb [3].
• RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells [11].
• Deletion of this gene (GABRB3) was found in AS and PWS patients with interstitial cytogenetic deletions [12].

Anatomical context of GABRB3

• Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts [11].
• Several genes/transcripts (for example, GABRA5, GABRB3) had increased expression in UPD cell lines compared with deletion, but less than controls indicating paternal bias [13].
• However, when present in lymphocytes of the cancer patients, all 3 loci change their replication mode: alleles of TP53 and D21S55 become asynchronous, whereas the early replicating allele of GABRB3 delays replication, leading to relaxation in the imprinted mode of replication [14].

Associations of GABRB3 with chemical compounds

• As the dopaminergic and GABAergic systems have been implicated in alcohol-related behaviors, variants of the D2 dopamine receptor (DRD2) and GABA(A) receptor beta3 subunit (GABRB3) genes were determined in a population-based association study of Caucasian non-alcoholic and alcoholic subjects [15].
• Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism [16].

Other interactions of GABRB3

• Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [17].
• DESIGN: Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor were investigated using association and linkage strategies [18].
• Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents) [19].
• However, when the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately [15].
• A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor beta 3 subunit (GABRB3) [20].

Analytical, diagnostic and therapeutic context of GABRB3

• An Alu-CA PCR method was used to isolate CA-repeat markers directly from yeast artificial chromosome (YAC) clones identified by probes IR4-3R (D15S11), LS6-1 (D15S113), and GABAA receptor B3 (GABRB3) [21].
• In a series of 18 individuals comprising parents of Angelman syndrome (AS) patients and AS patients with large deletions, microdeletions, and no deletions, we utilized fluorescence in situ hybridization (FISH) with genomic phage clones for loci D15S63 and GABRB3 for deletion detection of chromosome 15q11-q13 [22].
• Case-control study and transmission/disequilibrium tests of the genes encoding GABRA5 and GABRB3 in a Chinese population affected by childhood absence epilepsy [23].

References