GABRB3
Gamma-aminobutyric acid receptor subunit beta-3 is a
Gene
The GABRB3 gene is located on the long arm of
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
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
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000166206 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033676 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 9126483.
- ^ PMID 9545402.
- PMID 26056160.
- ^ PMID 1664410.
- ^ "Entrez Gene: GABRB3 gamma-aminobutyric acid (GABA) A receptor, beta 3".
- S2CID 35832564.
- ^ PMID 8095339.
- ^ S2CID 23459069.
- ^ PMID 17983671.
- S2CID 24096465.
- ^ "OMIM Entry - * 137192 - GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3". omim.org. Retrieved 2017-11-30.
- ^ PMID 24909990.
- ^ "Crystal structure of a human gamma-aminobutyric acid receptor, the GABA(A)R-beta3 homopentamer". Protein Data Bank. RCSB. January 28, 2014.
- PMID 17339270.
- S2CID 6172436.
- PMID 12819446.
- ISBN 978-1-118-05981-4.
- PMID 11920158.
- S2CID 13656488.
- PMID 18514161.
- PMID 16835263.
Further reading
- Saitoh S, Kubota T, Ohta T, Jinno Y, Niikawa N, Sugimoto T, Wagstaff J, Lalande M (February 1992). "Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABAA receptor beta 3-subunit gene". Lancet. 339 (8789): 366–367. S2CID 40634548.
- Wagstaff J, Knoll JH, Fleming J, Kirkness EF, Martin-Gallardo A, Greenberg F, Graham JM, Menninger J, Ward D, Venter JC (August 1991). "Localization of the gene encoding the GABAA receptor beta 3 subunit to the Angelman/Prader-Willi region of human chromosome 15". American Journal of Human Genetics. 49 (2): 330–337. PMID 1714232.
- Russek SJ, Farb DH (October 1994). "Mapping of the beta 2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABAA receptor isoform". Genomics. 23 (3): 528–533. PMID 7851879.
- Tögel M, Mossier B, Fuchs K, Sieghart W (April 1994). "gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties". The Journal of Biological Chemistry. 269 (17): 12993–12998. PMID 8175718.
- Kirkness EF, Fraser CM (February 1993). "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)". The Journal of Biological Chemistry. 268 (6): 4420–4428. PMID 8382702.
- Sinnett D, Wagstaff J, Glatt K, Woolf E, Kirkness EJ, Lalande M (June 1993). "High-resolution mapping of the gamma-aminobutyric acid receptor subunit beta 3 and alpha 5 gene cluster on chromosome 15q11-q13, and localization of breakpoints in two Angelman syndrome patients". American Journal of Human Genetics. 52 (6): 1216–1229. PMID 8389098.
- Glatt K, Glatt H, Lalande M (April 1997). "Structure and organization of GABRB3 and GABRA5". Genomics. 41 (1): 63–69. PMID 9126483.
- Meguro M, Mitsuya K, Sui H, Shigenami K, Kugoh H, Nakao M, Oshimura M (November 1997). "Evidence for uniparental, paternal expression of the human GABAA receptor subunit genes, using microcell-mediated chromosome transfer". Human Molecular Genetics. 6 (12): 2127–2133. PMID 9328477.
- Russek SJ (February 1999). "Evolution of GABA(A) receptor diversity in the human genome". Gene. 227 (2): 213–222. PMID 10023064.
- Buckley ST, Eckert AL, Dodd PR (September 2000). "Expression and distribution of GABAA receptor subtypes in human alcoholic cerebral cortex". Annals of the New York Academy of Sciences. 914 (1): 58–64. S2CID 13569188.
- 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. PMID 11920158.
- Buhr A, Bianchi MT, Baur R, Courtet P, Pignay V, Boulenger JP, Gallati S, Hinkle DJ, Macdonald RL, Sigel E (August 2002). "Functional characterization of the new human GABA(A) receptor mutation beta3(R192H)". Human Genetics. 111 (2): 154–160. S2CID 10982155.
- Trudell J (September 2002). "Unique assignment of inter-subunit association in GABA(A) alpha 1 beta 3 gamma 2 receptors determined by molecular modeling". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1565 (1): 91–96. PMID 12225856.
- Sarto I, Wabnegger L, Dögl E, Sieghart W (September 2002). "Homologous sites of GABA(A) receptor alpha(1), beta(3) and gamma(2) subunits are important for assembly". Neuropharmacology. 43 (4): 482–491. S2CID 140209788.
- Słopień A, Rajewski A, Budny B, Czerski P (2003). "[Evaluation of q11-q13 locus of chromosome 15 aberrations and polymorphisms in the B3 subunit of the GABA-A receptor gene (GABRB3) in autistic patients]". Psychiatria Polska. 36 (5): 779–791. PMID 12491987.
External links
- GABRB3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P28472 (Gamma-aminobutyric acid receptor subunit beta-3) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.