Biology:GABRB2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors.[1][2] Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short (β2S, β2S1, and β2S2). Alternatively spliced variants displayed similar but non-identical electrophysiological properties.[3] GABRB2 is subjected to positive selection and known to be both an alternative splicing and a recombination hotspot; it is regulated via epigenetic regulation including imprinting and gene and promoter methylation [4][5][6] GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer.

Structure

GABRB2 encodes the GABAA receptor beta-2 subunit. It is highly expressed in the brain with dominance in the gray matter.[7] In humans, it is located on chromosome 5q34, with 11 exons and 10 introns spanning more than 260 kb, and a promoter region ranging from 1000 bp upstream to 689 bp downstream of exon 1.[8] Alternative splicing of the gene product yields at least four isoforms, viz. β2-long (β2L), β2-short (β2S) and two additional short isoforms β2S1 and β2S2. These isoforms, composed of 512, 474, 313, and 372 amino acids respectively,[9] display dissimilar electrophysiological properties.[7] In mice, the corresponding Gabrb2 gene on chromosome 11A5 comprises 12 exons and 11 introns, and the two isoforms β2L and β2S from alternative splicing consisted of 512 and 474 amino acids respectively.[10] The β-2 subunit is a component of the ligand-gated chloride GABAA receptors which belongs to the Cys-loop superfamily.[11] Like all subunits of this family, it consists of an extracellular N-terminal domain containing a Cys-loop of 13 amino acids, four membrane-spanning domains (TM1-4) with a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain.[12] Five subunits from varied families (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) combine to form the heteropentameric GABAA receptor. TM2 from each subunit participates in the formation of the ion pore of the receptor, and α2β2γ2 is the major subtype in the brain that accounts for 43% of all GABAA receptors.[13][1]

Regulation

Phosphorylation is an important mechanism for the modulation of GABAA receptor function.[14] GABRB2 includes a consensus sequence for a calmodulin-dependent protein kinase II within exon 10 which is only expressed by β2L. As a result, upon repetitive stimulation, the β2L isoform-containing GABAA receptors are more vulnerable to run-down than those containing the short isoforms. Accordingly, ATP depletion reduces the inhibitory transmission of the GABAergic system due to GABAA receptors rundown through β2. Since this rundown occasioned by the presence of β2L would lead to improved maintenance of survival-favoring activities such as hunting and food gathering in the face of energy deprivation, it could be selected as an evolutionary advantage over the shorter isoforms.[15][4][7] Multiple lines of evidence confirmed the epigenetic regulation of GABRB2 gene expression via methylation and imprinting. GABRB2 mRNA expression level varied with germline genotypes, and with the gender of the parent in accord with the process of imprinting.[5][16][6][17]

Function

GABRB2 is highly expressed in the brain where it plays its major role.[18] In the immature brain, GABAA receptors participate in excitatory transmission,[19] which is important to synaptogenesis, neurogenesis, and the formation of the glutamatergic system.[20] In the mature brain, GABAA receptors fulfill their conventional inhibitory role, with the β2 subunits participating in some of the fastest inhibitory transmissions that prevent hyperexcitability, regulate the stress response of the hypothalamic-pituitary-adrenal axis, as well as pain signals mediated by the thalamus.[21][22] Moreover, GABRB2 is associated with cognitive function, energy regulation, time perception,[23] and the maintenance of efferent synaptic terminals in the mature ear.[24]

Clinical significance

GABRB2 is associated with a spectrum of neuropsychiatric disorders, and displays of differential gene expression between tumor and non tumor tissues.

Psychiatric disorders

Schizophrenia

Single nucleotide polymorphisms (SNPs) in GABRB2 were first associated with schizophrenia (SCZ) in Han Chinese, and confirmed subsequently for German, Portuguese, and Japanese SCZ patients.[25][26][27][28][29] Furthermore, their significant associations have been extended to cognitive function, psychosis, and neuroleptic-induced tardive dyskinesia in schizophrenics.[30][31][32] Recurrent copy number variations (CNVs) in GABRB2 were likewise associated with schizophrenia.[33] GABRB2 expression was decreased in genotype and age-dependent manners, with reduced β2L/β2S ratios in schizophrenics serving as a key determinant of the response of receptor function to the energy status.[7][4] The regulation of its expression by methylation and imprinting,[5][6][17] as well as its N-glycosylation of the β2-subunit, were altered in SCZ.[34] That GABRB2 is both a recombination hotspot and subject to positive selection could be an important factor in the widespread occurrence of SCZ.[4] Gabrb2-knockout mice displayed schizophrenia-like behavior including prepulse inhibition deficit and antisocial behavior that were ameliorated by the antipsychotic risperidone, strongly supporting the proposal based on postmortem SCZ brains that GABRB2 represents the key genetic factor in SCZ etiology.[35]

Other psychiatric disorders

GABRB2 was significantly associated with bipolar disorder, with a genotype-dependent decrease in GABRB2 mRNA levels weaker than that observed in SCZ.[3][36][37][38] In major depressive disorder, the expressions of GABAA subunit genes were altered,[39] and the expression of GABRB2 was significantly decreased in the anterior cingulate cortex, in the postmortem brains of patients.[40] The expression of GABRB2 was significantly increased in the internet gaming disorder group, and GABRB2 was the downstream target for two circulating microRNA, viz. hsa-miR-26b-5p and hsa-miR-652-3p, which were significantly downregulated in these subjects.[41] The GABAergic system was suggested to be a factor in the physiopathology of premenstrual dysphoric disorder (PMDD).[42] GABA levels were altered in the brain of PMDD patients.[43] Two highly recurrent copy number variations in GABRB2 were associated with PMDD in Chinese and German patients, providing thereby a possible explanation of part of the complex psychological symptoms of PMDD.[33]

Drug dependence

SNPs in GABRB2 were significantly associated with alcohol dependence and consumption in Southwestern Native Americans, Finnish, Scottish, and Sidney populations.[44][45][46] Chronic alcohol administration induced an increase in the expression of Gabrb2 in a rat model.[47] and sleep time was decreased in Gabrb2 knockout mice.[48] SNPs in GABRB2 were significantly associated with heroin addiction in African American subjects.[49] Haplotypes in GABRB2 yielded a significant association with heroin dependence in the Chinese population.[50]

Neurological disorders

Epilepsy

Numerous de novo mutations in GABRB2 were associated with infantile and early childhood epileptic encephalopathy (IECEE).[51][52][53][54][55] As well, SNPs in GABRB2 were significantly associated with epilepsy in the North Indian population.[56] Moreover, Gabrb2 knockout mice displayed audiogenic epilepsy, which further confirmed the contribution of GABRB2 to the etiology of epilepsy.[35]

Autism spectrum disorder

The density of GABAA receptors showed a significant reduction in autistic brains.[57] and SNPs in GABRB2 were significantly associated with autism.[58] De novo pathogenic mutations in the GABRB2 gene contribute to the physiopathology of Rett syndrome.[59][60] β2 subunit mRNA expression level was subjected to significant upregulation in a mouse model of Rett syndrome [61]

Neurodegenerative disorders

Deficits in the GABergic system and decreased levels of GABA were reported in Alzheimer's disease (AD).[62] An SNP near GABRB2 was associated with AD.[63] Two SNPs in GABRB2 were significantly associated with frontotemporal dementia (FTD) risk, and GABRB2 was downregulated in a cellular system of FTD and a mouse model of tauopathy.[64][65]

Cancer

Genomic classifiers including GABRB2 could differentiate correctly between malignant and benign nodules.[66][67] and GABRB2 alone or in combination with other genes correctly distinguished between malignant and benign tumors.[68][69] GABRB2 was upregulated and hypomethylated in papillary thyroid carcinoma. The downregulation of GABRB2 enhanced the apoptotic cell death and decreased proliferation, migration, and invasiveness of thyroid cancer cells.[70][71] GABRB2 was upregulated in adrenocortical carcinoma and salivary gland cancer,[72][73] but downregulated in patients with colorectal cancer, brain tumors, kidney renal clear cell carcinoma and lung cancer [74][75][76][77][78][79]

Therapeutic implications

The β2 subunit-containing GABAA receptors are more sensitive to GABA.[80] Tyrosine and proline residues in the Cys-loop of this subunit were important elements in the binding and response to GABA,[81][82] and the subunit also mediated the receptor binding of alcohol and anesthetics, anticonvulsive activity of loreclezole, hypothermic response to etomidate, as well as the sedative effects of both etomidate and loreclezole.[2][83][84] It was identified as a target for the endocannabinoid 2-arachidonylglycerol,[85] and Gabrb2 expression was upregulated by the antiepileptic drug qingyangshenylycosides and downregulated by the opioid oxycodone [86][87] The wide-ranging involvement of the GABRB2 and its gene products in neuropsychiatric pharmacology are in accord with their central roles in inhibitory signaling in the brain.

See also

Notes

References

  1. ↑ 1.0 1.1 "Which GABAA-receptor subtypes really occur in the brain?". Trends in Neurosciences 19 (4): 139–43. April 1996. doi:10.1016/s0166-2236(96)80023-3. PMID 8658597. 
  2. ↑ 2.0 2.1 "A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics". The Journal of Pharmacology and Experimental Therapeutics 335 (3): 600–6. December 2010. doi:10.1124/jpet.110.170472. PMID 20826568. 
  3. ↑ 3.0 3.1 "Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders". PLOS ONE 4 (9): e6977. September 2009. doi:10.1371/journal.pone.0006977. PMID 19763268. 
  4. ↑ 4.0 4.1 4.2 4.3 "Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene". PLOS ONE 2 (5): e462. May 2007. doi:10.1371/journal.pone.0000462. PMID 17520021. 
  5. ↑ 5.0 5.1 5.2 "Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit". Molecular Psychiatry 16 (5): 557–68. May 2011. doi:10.1038/mp.2010.47. PMID 20404824. 
  6. ↑ 6.0 6.1 6.2 "Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders". Schizophrenia Research 134 (2–3): 260–6. February 2012. doi:10.1016/j.schres.2011.11.029. PMID 22206711. 
  7. ↑ 7.0 7.1 7.2 7.3 "Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia". Molecular Psychiatry 11 (12): 1092–105. December 2006. doi:10.1038/sj.mp.4001899. PMID 16983389. 
  8. ↑ "GABRB2 gamma-aminobutyric acid type A receptor subunit beta2 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=2561. 
  9. ↑ "GABRB2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Homo sapiens (Human) - GABRB2 gene & protein" (in en). https://www.uniprot.org/uniprot/P47870. 
  10. ↑ "Gabrb2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Mus musculus (Mouse) - Gabrb2 gene & protein" (in en). https://www.uniprot.org/uniprot/P63137. 
  11. ↑ "Mutant GABAA receptor subunits in genetic (Idiopathic) epilepsy". Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Progress in Brain Research. 213. 2014. pp. 55–85. doi:10.1016/B978-0-444-63326-2.00003-X. ISBN 9780444633262. 
  12. ↑ "Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil". Journal of Molecular Modeling 15 (9): 1145–53. September 2009. doi:10.1007/s00894-009-0477-2. PMID 19238461. 
  13. ↑ "Identification of the sites for CaMK-II-dependent phosphorylation of GABA(A) receptors". The Journal of Biological Chemistry 282 (24): 17855–65. June 2007. doi:10.1074/jbc.M611533200. PMID 17442679. 
  14. ↑ "Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement". The Journal of Biological Chemistry 277 (48): 46020–5. November 2002. doi:10.1074/jbc.M207663200. PMID 12324466. 
  15. ↑ "Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain". Proceedings of the National Academy of Sciences of the United States of America 101 (27): 10183–8. July 2004. doi:10.1073/pnas.0403683101. PMID 15218107. Bibcode: 2004PNAS..10110183P. 
  16. ↑ "DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms". Genes, Brain and Behavior 15 (8): 702–710. November 2016. doi:10.1111/gbb.12315. PMID 27509263. 
  17. ↑ 17.0 17.1 "Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia". Journal of Psychiatric Research 88: 9–17. May 2017. doi:10.1016/j.jpsychires.2016.12.019. PMID 28063323. 
  18. ↑ "Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics". Molecular & Cellular Proteomics 13 (2): 397–406. February 2014. doi:10.1074/mcp.M113.035600. PMID 33498127. 
  19. ↑ "GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations". Physiological Reviews 87 (4): 1215–84. October 2007. doi:10.1152/physrev.00017.2006. PMID 17928584. 
  20. ↑ "GABA receptors precede glutamate receptors in hypothalamic development; differential regulation by astrocytes". Journal of Neurophysiology 74 (4): 1473–84. October 1995. doi:10.1152/jn.1995.74.4.1473. PMID 8989386. 
  21. ↑ "AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects". PLOS Computational Biology 10 (6): e1003627. June 2014. doi:10.1371/journal.pcbi.1003627. PMID 24901472. Bibcode: 2014PLSCB..10E3627Z. 
  22. ↑ "Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration". Annals of the New York Academy of Sciences 1018 (1): 35–45. June 2004. doi:10.1196/annals.1296.004. PMID 15240350. Bibcode: 2004NYASA1018...35H. 
  23. ↑ "Genetic influence alters the brain synchronism in perception and timing". Journal of Biomedical Science 25 (1): 61. August 2018. doi:10.1186/s12929-018-0463-z. PMID 30086746. 
  24. ↑ "Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta". The Journal of Neuroscience 26 (40): 10315–26. October 2006. doi:10.1523/JNEUROSCI.2395-06.2006. PMID 17021187. 
  25. ↑ "Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia". Molecular Psychiatry 9 (6): 603–8. June 2004. doi:10.1038/sj.mp.4001461. PMID 14699426. 
  26. ↑ "Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population". Biochemical and Biophysical Research Communications 334 (3): 817–23. September 2005. doi:10.1016/j.bbrc.2005.06.167. PMID 16023997. 
  27. ↑ "GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes". Biological Psychiatry 61 (5): 653–60. March 2007. doi:10.1016/j.biopsych.2006.05.003. PMID 16950232. 
  28. ↑ "Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia". Molecular Psychiatry 10 (12): 1074–88, 1057. December 2005. doi:10.1038/sj.mp.4001739. PMID 16172613. 
  29. ↑ "Analysis of GABRB2 association with schizophrenia in German population with DNA sequencing and one-label extension method for SNP genotyping". Clinical Biochemistry 39 (3): 210–8. March 2006. doi:10.1016/j.clinbiochem.2006.01.009. PMID 16472798. 
  30. ↑ "Social cognitive role of schizophrenia candidate gene GABRB2". PLOS ONE 8 (4): e62322. 24 April 2013. doi:10.1371/journal.pone.0062322. PMID 23638040. Bibcode: 2013PLoSO...862322T. 
  31. ↑ "The association of GABRB2 SNPs with cognitive function in schizophrenia". European Archives of Psychiatry and Clinical Neuroscience 270 (4): 443–449. June 2020. doi:10.1007/s00406-019-00985-3. PMID 30706170. 
  32. ↑ "Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia". Pharmacogenetics and Genomics 18 (4): 317–23. April 2008. doi:10.1097/FPC.0b013e3282f70492. PMID 18334916. 
  33. ↑ 33.0 33.1 "Highly Recurrent Copy Number Variations in GABRB2 Associated With Schizophrenia and Premenstrual Dysphoric Disorder". Frontiers in Psychiatry 11: 572. 30 June 2020. doi:10.3389/fpsyt.2020.00572. PMID 32695026. 
  34. ↑ "N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia". Neuropsychopharmacology 39 (3): 528–37. February 2014. doi:10.1038/npp.2013.190. PMID 23917429. 
  35. ↑ 35.0 35.1 "Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation". Translational Psychiatry 8 (1): 128. July 2018. doi:10.1038/s41398-018-0176-9. PMID 30013074. 
  36. ↑ "Family-based association study of lithium-related and other candidate genes in bipolar disorder". Archives of General Psychiatry 65 (1): 53–61. January 2008. doi:10.1001/archgenpsychiatry.2007.15. PMID 18180429. 
  37. ↑ "Independent evidence for the selective influence of GABA(A) receptors on one component of the bipolar disorder phenotype". Molecular Psychiatry 16 (6): 587–9. June 2011. doi:10.1038/mp.2010.67. PMID 20548298. 
  38. ↑ "GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations". Biochemical Society Transactions 37 (Pt 6): 1415–8. December 2009. doi:10.1042/BST0371415. PMID 19909288. 
  39. ↑ "Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression". Proceedings of the National Academy of Sciences of the United States of America 102 (43): 15653–8. October 2005. doi:10.1073/pnas.0507901102. PMID 16230605. Bibcode: 2005PNAS..10215653C. 
  40. ↑ "Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients". Journal of Affective Disorders 138 (3): 494–502. May 2012. doi:10.1016/j.jad.2012.01.013. PMID 22357337. 
  41. ↑ "Circulating MicroRNA Expression Levels Associated With Internet Gaming Disorder". Frontiers in Psychiatry 9: 81. 12 March 2018. doi:10.3389/fpsyt.2018.00081. PMID 29593587. 
  42. ↑ "Premenstrual Syndrome and Premenstrual Dysphoric Disorder". American Family Physician 94 (3): 236–40. August 2016. PMID 27479626. 
  43. ↑ "Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: a 3T proton magnetic resonance spectroscopy study". Psychiatry Research 231 (1): 64–70. January 2015. doi:10.1016/j.pscychresns.2014.10.020. PMID 25465316. 
  44. ↑ "Genetical genomic determinants of alcohol consumption in rats and humans". BMC Biology 7 (1): 70. October 2009. doi:10.1186/1741-7007-7-70. PMID 19874574. 
  45. ↑ "Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population". Molecular Psychiatry 4 (6): 539–44. November 1999. doi:10.1038/sj.mp.4000554. PMID 10578235. 
  46. ↑ "Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster". Archives of General Psychiatry 62 (1): 47–55. January 2005. doi:10.1001/archpsyc.62.1.47. PMID 15630072. 
  47. ↑ "Bidirectional alterations of GABA(A) receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal". Journal of Neurochemistry 69 (1): 126–30. July 1997. doi:10.1046/j.1471-4159.1997.69010126.x. PMID 9202302. 
  48. ↑ "Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs". The Journal of Pharmacology and Experimental Therapeutics 304 (1): 30–6. January 2003. doi:10.1124/jpet.102.042960. PMID 12490572. 
  49. ↑ "Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry". Progress in Neuro-Psychopharmacology & Biological Psychiatry 64: 118–23. January 2016. doi:10.1016/j.pnpbp.2015.08.003. PMID 26277529. 
  50. ↑ "GABRB2 Haplotype Association with Heroin Dependence in Chinese Population". PLOS ONE 10 (11): e0142049. 12 November 2015. doi:10.1371/journal.pone.0142049. PMID 26561861. Bibcode: 2015PLoSO..1042049K. 
  51. ↑ "High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies". American Journal of Human Genetics 101 (5): 664–685. November 2017. doi:10.1016/j.ajhg.2017.09.008. PMID 29100083. 
  52. ↑ "A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy". Journal of Medical Genetics 54 (3): 202–211. March 2017. doi:10.1136/jmedgenet-2016-104083. PMID 27789573. 
  53. ↑ "Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study". The Lancet. Neurology 17 (8): 699–708. August 2018. doi:10.1016/S1474-4422(18)30215-1. PMID 30033060. http://openaccess.sgul.ac.uk/110054/1/LancetNeurology.revision.final.docx. 
  54. ↑ "Novel genetic causes for cerebral visual impairment". European Journal of Human Genetics 24 (5): 660–5. May 2016. doi:10.1038/ejhg.2015.186. PMID 26350515. 
  55. ↑ "A novel variant in GABRB2 associated with intellectual disability and epilepsy". American Journal of Medical Genetics. Part A 164A (11): 2914–21. November 2014. doi:10.1002/ajmg.a.36714. PMID 25124326. 
  56. ↑ "Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population". Clinica Chimica Acta; International Journal of Clinical Chemistry 412 (13–14): 1244–8. June 2011. doi:10.1016/j.cca.2011.03.018. PMID 21420396. 
  57. ↑ "Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study". Journal of Autism and Developmental Disorders 31 (6): 537–43. December 2001. doi:10.1023/a:1013238809666. PMID 11814263. 
  58. ↑ "Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism". American Journal of Human Genetics 77 (3): 377–88. September 2005. doi:10.1086/433195. PMID 16080114. 
  59. ↑ "Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes". International Journal of Molecular Sciences 20 (15): 3621. July 2019. doi:10.3390/ijms20153621. PMID 31344879. 
  60. ↑ "Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2". Genetics in Medicine 19 (1): 13–19. January 2017. doi:10.1038/gim.2016.42. PMID 27171548. 
  61. ↑ "Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome". Neurobiology of Disease 109 (Pt A): 25–32. January 2018. doi:10.1016/j.nbd.2017.09.006. PMID 28927958. 
  62. ↑ "Implications of GABAergic Neurotransmission in Alzheimer's Disease". Frontiers in Aging Neuroscience 8: 31. 23 February 2016. doi:10.3389/fnagi.2016.00031. PMID 26941642. 
  63. ↑ "Genome-wide association study identifies two loci influencing plasma neurofilament light levels". BMC Medical Genomics 11 (1): 47. May 2018. doi:10.1186/s12920-018-0364-8. PMID 29747637. 
  64. ↑ "Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP". Translational Psychiatry 8 (1): 265. December 2018. doi:10.1038/s41398-018-0319-z. PMID 30546007. 
  65. ↑ "A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology". Cell Reports 10 (4): 633–44. February 2015. doi:10.1016/j.celrep.2014.12.041. PMID 25620700. 
  66. ↑ "Whole-transcriptome profiling of thyroid nodules identifies expression-based signatures for accurate thyroid cancer diagnosis". The Journal of Clinical Endocrinology and Metabolism 98 (10): 4072–9. October 2013. doi:10.1210/jc.2013-1991. PMID 23928671. 
  67. ↑ "Preoperative diagnosis of benign thyroid nodules with indeterminate cytology". The New England Journal of Medicine 367 (8): 705–15. August 2012. doi:10.1056/NEJMoa1203208. PMID 22731672. 
  68. ↑ "High Diagnostic Accuracy Based on CLDN10, HMGA2, and LAMB3 Transcripts in Papillary Thyroid Carcinoma". The Journal of Clinical Endocrinology and Metabolism 100 (6): E890-9. June 2015. doi:10.1210/jc.2014-4053. PMID 25867809. 
  69. ↑ "A panel of four genes accurately differentiates benign from malignant thyroid nodules". Journal of Experimental & Clinical Cancer Research 35 (1): 169. October 2016. doi:10.1186/s13046-016-0447-3. PMID 27793213. 
  70. ↑ "Integrated data analysis reveals potential drivers and pathways disrupted by DNA methylation in papillary thyroid carcinomas". Clinical Epigenetics 9 (1): 45. December 2017. doi:10.1186/s13148-017-0346-2. PMID 28469731. 
  71. ↑ "GABRB2 plays an important role in the lymph node metastasis of papillary thyroid cancer". Biochemical and Biophysical Research Communications 492 (3): 323–330. October 2017. doi:10.1016/j.bbrc.2017.08.114. PMID 28859983. 
  72. ↑ "A Targeted Bioinformatics Assessment of Adrenocortical Carcinoma Reveals Prognostic Implications of GABA System Gene Expression". International Journal of Molecular Sciences 21 (22): 8485. November 2020. doi:10.3390/ijms21228485. PMID 33187258. 
  73. ↑ "Identification of differentially expressed genes in salivary adenoid cystic carcinoma cells associated with metastasis". Archives of Medical Science 12 (4): 881–8. August 2016. doi:10.5114/aoms.2016.60973. PMID 27478471. 
  74. ↑ "Analysis of Matched Tumor and Normal Profiles Reveals Common Transcriptional and Epigenetic Signals Shared across Cancer Types". PLOS ONE 10 (11): e0142618. 10 November 2015. doi:10.1371/journal.pone.0142618. PMID 26555223. Bibcode: 2015PLoSO..1042618G. 
  75. ↑ "A predictive analysis approach for paediatric and adult high-grade glioma: miRNAs and network insight". Annals of Translational Medicine 8 (5): 242. March 2020. doi:10.21037/atm.2020.01.12. PMID 32309389. 
  76. ↑ "Comprehensive Analysis of Core Genes and Potential Mechanisms in Rectal Cancer". Journal of Computational Biology 26 (11): 1262–1277. November 2019. doi:10.1089/cmb.2019.0073. PMID 31211595. 
  77. ↑ "Differential gene expression profiling in human brain tumors". Physiological Genomics 5 (1): 21–33. February 2001. doi:10.1152/physiolgenomics.2001.5.1.21. PMID 11161003. 
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  79. ↑ "Distinct diagnostic and prognostic values of γ-aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma". Oncology Letters 20 (1): 275–291. July 2020. doi:10.3892/ol.2020.11573. PMID 32565954. 
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