GABRB3

Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the GABRB3 gene. It is located within the 15q12 region in the human genome and spans 250kb.[5] This gene includes 10 exons within its coding region.[5] Due to alternative splicing, the gene codes for many protein isoforms, all being subunits in the GABAA receptor, a ligand-gated ion channel. The beta-3 subunit is expressed at different levels within the cerebral cortex, hippocampus, cerebellum, thalamus, olivary body and piriform cortex of the brain at different points of development and maturity.[6] GABRB3 deficiencies are implicated in many human neurodevelopmental disorders and syndromes such as Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. The effects of methaqualone[7] and etomidate are mediated through GABBR3 positive allosteric modulation.

GABRB3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGABRB3, ECA5, gamma-aminobutyric acid type A receptor beta3 subunit, EIEE43, gamma-aminobutyric acid type A receptor subunit beta3, DEE43
External IDsOMIM: 137192 MGI: 95621 HomoloGene: 633 GeneCards: GABRB3
Orthologs
SpeciesHumanMouse
Entrez

2562

14402

Ensembl

ENSG00000166206

ENSMUSG00000033676

UniProt

P28472

P63080

RefSeq (mRNA)

NM_000814
NM_001191320
NM_001191321
NM_001278631
NM_021912

NM_001038701
NM_008071

RefSeq (protein)

NP_000805
NP_001178249
NP_001178250
NP_001265560
NP_068712

NP_001033790
NP_032097

Location (UCSC)Chr 15: 26.54 – 26.94 MbChr 7: 57.07 – 57.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

The GABRB3 gene is located on the long arm of chromosome 15, within the q12 region in the human genome. It is located in a gene cluster, with two other genes, GABRG3 and GABRA5. GABRB3 was the first gene to be mapped to this particular region.[8] It spans approximately 250kb and includes 10 exons within its coding region, as well as two additional alternative first exons that encode for signaling peptides.[5] Alternatively spliced transcript variants encoding isoforms with distinct signal peptides have been described.[9] This gene is located within an imprinting region that spans the 15q11-13 region. Its sequence is considerably longer than the two other genes found within its gene cluster due to a large 150kb intron it carries. A pattern is observed in GABRB3 gene replication, in humans the maternal allele is replicated later than the paternal allele.[10] The reasoning and implications of this pattern are unknown.

When comparing the human beta-3 subunit's genetic sequence with other vertebrate beta-3 subunit sequences, there is a high level of genetic conservation.[8] In mice the Gabrb3 gene is located on chromosome 7 of its genome[11] in a similar gene cluster style with some of the other subunits of the GABAA receptor.[12]

Function

GABRB3 encodes a member of the ligand-gated ion channel family. The encoded protein is one of at least 13 distinct subunits of a multisubunit chloride channel that serves as the receptor for gamma-aminobutyric acid, the major inhibitory neurotransmitter of the nervous system. The two other genes in the gene cluster both encode for related subunits of the family. During development, when the GABRB3 subunit functions optimally, its role in the GABAA receptor allows for proliferation, migration, and differentiation of precursor cells that lead to the proper development of the brain.[13] GABAA receptor function is inhibited by zinc ions. The ions bind allosterically to the receptor, a mechanism that is critically dependent on the receptor subunit composition.[14]

De novo heterozygous missense mutations within a highly conserved region of the GABRB3 gene can decrease the peak current amplitudes of neurons or alter the kinetic properties of the channel.[15] This results in the loss of the inhibitory properties of the receptor.

The beta-3 subunit has very similar function to the human version of the subunit.[11]

Structure

The crystal structure of a human β3 homopentamer was published in 2014.[16][17] The study of the crystal structure of the human β3 homopentamer revealed unique qualities that are only observed in eukaryotic cysteine-loop receptors. The characterization of the GABAA receptor and subunits helps with the mechanistic determination of mutations within the subunits and what direct effect the mutations may have on the protein and its interactions.[16]

Expression

The expression of GABRB3 is not constant among all cells or at all stages of development. The distribution of expression of the GABAA receptor subunits (GABRB3 included) during development indicates that GABA may function as a neurotrophic factor, impacting neural differentiation, growth, and circuit organization. The expression of the beta-3 subunit reaches peak at different times in different locations of the brain, during development. The highest expression of Gabrb3 in mice, within the cerebral cortex and hippocampus are reached prenatally, while they are reached postnatally in the cerebellar cortex. After the highest peak of expression, Gabrb3 expression is down-regulated substantially in the thalamus and inferior olivary body of the mouse. By adulthood, the level of expression in the cerebral cortex and hippocampus drops below developmental expression levels, but the expression in the cerebellum does not change postnatally. The highest levels of Gabrb3 expression in the mature mouse brain occur in the Purkinje and granule cells of the cerebellum, the hippocampus, and the piriform cortex.[6]

In humans, the beta-3 subunit, as well as the subunits of its two neighbouring genes (GABRG3 and GABRA5), are bi-allelically expressed within the cerebral cortex, indicating that the gene is not subjected to imprinting within those cells.[18]

Imprinting Patterns

Due to the location of GABRB3 in the 15q11-13 imprinting region found in humans, this gene is subject to imprinting depending on the location and the cells developmental state. Imprinting is not present in the mouse brain, having an equal expression from maternal and paternal alleles.[11]

Regulation

Phosphorylation of the GABAA by cAMP-dependent protein kinase (PKA) has a regulatory effect dependent on the beta subunit involved. The mechanism by which the kinase is targeted towards the bata-3 subunit is unknown. AKAP79/150 binds directly to the GABRB3 subunit, which is critical for its own phosphorylation, mediated by PKA.[19]

Gabrb3 shows significantly reduced expression postnatally, when mice are deficient in MECP2. When the MECP2 gene is knocked out, the expression of Gabrb3 is reduced, suggesting a relationship of positive regulation between the two genes.[13]

Clinical significance

Mutations in this gene may be associated with the pathogenesis of Angelman syndrome, nonsyndromic orofacial clefts, epilepsy and autism. The GABRB3 gene has been associated with savant skills accompanying such disorders.[20]

In mice, the knockout mutation of Gabrb3 causes severe neonatal mortality with the cleft palate phenotype present, the survivors experiencing hyperactivity, lack of coordination and suffering with epileptic seizures.[12] These mice also exhibit changes to the vestibular system within the ear, resulting in poor swimming skills, difficulty in walking on grid floors, and are found to run in circles erratically.[13]

Angelman syndrome

Deletion of the GABRB3 gene results in Angelman syndrome in humans, depending on the parental origin of the deletion.[13] Deletion of the paternal allele of GABRB3 has no known implications with this syndrome, while deletion of the maternal GABRB3 allele results in development of the syndrome.[21]

Nonsyndromic Orofacial Clefting

There is a strong association between GABRB3 expression levels and proper palate development. A disturbance in GABRB3 expression can be lined to the malformation of nonsyndromic cleft lip with or without cleft palate. Cleft lip and palate have also been observed in children who have inverted duplications encompassing the GABRB3 locus. Knockout of the beta-3 subunit in mice results in clefting of the secondary palate. Normal facial characteristics can be restored through the insertion of a Gabrb3 transgene into the mouse genome, making the Gabrb3 gene primarily responsible for cleft palate formation.[12]

Autism Spectrum Disorder

Duplications of the Prader-Willi/Angelman syndrome region, also known as the imprinting region (15q11-13) that encompasses the GABRB3 gene are present in some patients diagnosed with Autism.[6] These patients exhibit classic symptoms that are associated with the disorder. Duplications of the 15q11-13 region displayed in autistic patients are almost always of maternal origin (not paternal) and account for 1–2% of diagnosed autism disorder cases.[13] This gene is also a candidate for autism because of the physiological response that benzodiazepine has on the GABA-A receptor, when used to treat seizures and anxiety disorders.[6]

The Gabrb3 gene deficient mouse has been proposed as a model of autism spectrum disorder.[13] These mice exhibit similar phenotypic symptoms such as non-selective attention, deficits in a variety of exploratory parameters, sociability, social novelty, nesting and lower rearing frequency as can be equated to characteristics found in patients diagnosed with autism spectrum disorder. When studying Gabrb3 deficient mice, significant hypoplasia of the cerebellar vermis was observed.[13]

There is an unknown association between autism and the 155CA-2 locus, located within an intron in GABRB3.[22]

Epilepsy/Childhood absence epilepsy

Defects in GABA transmission has often been implicated in epilepsy within animal models and human syndromes.[23] Patients that are diagnosed with Angelman syndrome and have a deletion of the GABRB3 gene exhibit absence seizures.[24] Reduced expression of the beta-3 subunit is a potential contributor to childhood absence epilepsy.[25]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000166206 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000033676 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Glatt K, Glatt H, Lalande M (April 1997). "Structure and organization of GABRB3 and GABRA5". Genomics. 41 (1): 63–69. doi:10.1006/geno.1997.4639. PMID 9126483.
  6. Cook EH, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E (May 1998). "Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers". American Journal of Human Genetics. 62 (5): 1077–1083. doi:10.1086/301832. PMC 1377089. PMID 9545402.
  7. Hammer H, Bader BM, Ehnert C, Bundgaard C, Bunch L, Hoestgaard-Jensen K, Schroeder OH, Bastlund JF, Gramowski-Voß A, Jensen AA (August 2015). "A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)". Molecular Pharmacology. 88 (2): 401–420. doi:10.1124/mol.115.099291. PMC 4518083. PMID 26056160.
  8. Wagstaff J, Chaillet JR, Lalande M (December 1991). "The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7". Genomics. 11 (4): 1071–1078. doi:10.1016/0888-7543(91)90034-C. PMID 1664410.
  9. "Entrez Gene: GABRB3 gamma-aminobutyric acid (GABA) A receptor, beta 3".
  10. Knoll JH, Cheng SD, Lalande M (January 1994). "Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region". Nature Genetics. 6 (1): 41–46. doi:10.1038/ng0194-41. PMID 8136833. S2CID 35832564.
  11. Nicholls RD, Gottlieb W, Russell LB, Davda M, Horsthemke B, Rinchik EM (March 1993). "Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11-q13 syndromes by fine-structure homology mapping in the mouse". Proceedings of the National Academy of Sciences of the United States of America. 90 (5): 2050–2054. Bibcode:1993PNAS...90.2050N. doi:10.1073/pnas.90.5.2050. PMC 46018. PMID 8095339.
  12. Scapoli L, Martinelli M, Pezzetti F, Carinci F, Bodo M, Tognon M, Carinci P (January 2002). "Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate". Human Genetics. 110 (1): 15–20. doi:10.1007/s00439-001-0639-5. PMID 11810291. S2CID 23459069.
  13. DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (March 2008). "Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder". Behavioural Brain Research. 187 (2): 207–220. doi:10.1016/j.bbr.2007.09.009. PMC 2684890. PMID 17983671.
  14. Hosie AM, Dunne EL, Harvey RJ, Smart TG (April 2003). "Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity". Nature Neuroscience. 6 (4): 362–369. doi:10.1038/nn1030. PMID 12640458. S2CID 24096465.
  15. "OMIM Entry - * 137192 - GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3". omim.org. Retrieved 2017-11-30.
  16. Miller PS, Aricescu AR (August 2014). "Crystal structure of a human GABAA receptor". Nature. 512 (7514): 270–275. Bibcode:2014Natur.512..270M. doi:10.1038/nature13293. PMC 4167603. PMID 24909990.
  17. "Crystal structure of a human gamma-aminobutyric acid receptor, the GABA(A)R-beta3 homopentamer". Protein Data Bank. RCSB. January 28, 2014.
  18. Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM (March 2007). "15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders". Human Molecular Genetics. 16 (6): 691–703. doi:10.1093/hmg/ddm014. PMC 1934608. PMID 17339270.
  19. Brandon NJ, Jovanovic JN, Colledge M, Kittler JT, Brandon JM, Scott JD, Moss SJ (January 2003). "A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABA(A) receptors by cAMP-dependent protein kinase via selective interaction with receptor beta subunits". Molecular and Cellular Neurosciences. 22 (1): 87–97. doi:10.1016/S1044-7431(02)00017-9. PMID 12595241. S2CID 6172436.
  20. Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS (July 2003). "Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13". Journal of the American Academy of Child and Adolescent Psychiatry. 42 (7): 856–863. doi:10.1097/01.CHI.0000046868.56865.0F. PMID 12819446.
  21. Allison, Lizabeth A. (2012). Fundamental Molecular Biology. New Jersey: John Wiley & Sons, Inc. p. 363. ISBN 978-1-118-05981-4.
  22. Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH, Fang Y, Song CY, Vitale R (2002). "Association between a GABRB3 polymorphism and autism". Molecular Psychiatry. 7 (3): 311–316. doi:10.1038/sj.mp.4001011. PMID 11920158.
  23. DeLorey TM, Olsen RW (September 1999). "GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man". Epilepsy Research. 36 (2–3): 123–132. doi:10.1016/s0920-1211(99)00046-7. PMID 10515160. S2CID 13656488.
  24. Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, Castro-Ortega R, Martinez-Juarez IE, Pascual-Castroviejo I, Machado-Salas J, Silva R, Bailey JN, Bai D, Ochoa A, Jara-Prado A, Pineda G, Macdonald RL, Delgado-Escueta AV (June 2008). "Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy". American Journal of Human Genetics. 82 (6): 1249–1261. doi:10.1016/j.ajhg.2008.04.020. PMC 2427288. PMID 18514161.
  25. Urak L, Feucht M, Fathi N, Hornik K, Fuchs K (August 2006). "A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity". Human Molecular Genetics. 15 (16): 2533–2541. doi:10.1093/hmg/ddl174. PMID 16835263.

Further reading

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