Gamma-aminobutyric acid receptor subunit beta-3 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''GABRB3''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It is located within the 15q12 region in the human

genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...

and spans 250kb. This gene includes 10

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s within its coding region. Due to

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

, the gene codes for many

protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s, all being subunits in the GABA_A receptor, a ligand-gated ion channel. The beta-3 subunit is expressed at different levels within the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

olivary body The olivary bodies or simply olives (Latin ''oliva'' and ''olivae'', singular and plural, respectively) are a pair of prominent oval structures on either side of the medullary pyramids in the medulla oblongata, medulla, the lower portion of the br ...

and piriform cortex of the brain at different points of development and maturity. GABRB3 deficiencies are implicated in many human

neurodevelopmental disorder Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...

s and syndromes such as

Angelman syndrome Angelman syndrome (AS) is a genetic disorder that affects approximately 1 in 15,000 individuals. AS impairs the function of the nervous system, producing symptoms, such as severe intellectual disability, developmental disability, limited to no ...

, Prader-Willi syndrome, nonsyndromic orofacial clefts,

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

and

autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

. The effects of

methaqualone Methaqualone is a hypnotic sedative. It was sold under the brand names Quaalude ( ) and Sopor among others, which contained 300 mg of methaqualone, and sold as a combination drug under the brand name Mandrax, which contained 250 mg me ...

and

etomidate Etomidate (United States Adopted Name, USAN, International Nonproprietary Name, INN, British Approved Name, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for ...

are mediated through GABBR3 positive allosteric modulation.

Gene

The GABRB3 gene is located on the long arm of

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

15, within the q12 region in the human genome. It is located in a

gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...

, with two other genes, GABRG3 and GABRA5. GABRB3 was the first gene to be mapped to this particular region. 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.

Alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

transcript variants encoding isoforms with distinct signal peptides have been described. 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 An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

it carries. A pattern is observed in GABRB3 gene replication, in humans the maternal

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

is replicated later than the paternal allele. The reasoning and implications of this pattern are unknown. When comparing the human beta-3 subunit's genetic sequence with other

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

beta-3 subunit sequences, there is a high level of genetic conservation. In mice the Gabrb3 gene is located on chromosome 7 of its genome in a similar gene cluster style with some of the other subunits of the GABA_A receptor.

Function

GABRB3 encodes a member of the

ligand-gated ion channel Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as sodium, Na+, potassium, K+, calcium, Ca2+, and/or chloride, Cl− to ...

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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

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 GABA_A receptor allows for proliferation, migration, and differentiation of precursor cells that lead to the proper development of the brain. GABA_A 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. ''De novo''

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

s within a highly conserved region of the GABRB3 gene can decrease the peak current amplitudes of

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s or alter the kinetic properties of the channel. 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.

Structure

The

crystal structure In crystallography, crystal structure is a description of ordered arrangement of atoms, ions, or molecules in a crystalline material. Ordered structures occur from intrinsic nature of constituent particles to form symmetric patterns that repeat ...

of a human β3 homopentamer was published in 2014. 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 GABA_A 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.

Expression

The expression of GABRB3 is not constant among all cells or at all stages of development. The distribution of expression of the GABA_A receptor subunits (GABRB3 included) during development indicates that GABA may function as a

neurotrophic factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...

, 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

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 A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

occur in the Purkinje and granule cells of the cerebellum, the hippocampus, and the piriform cortex. 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.

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 A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

brain, having an equal expression from maternal and paternal alleles.

Regulation

Phosphorylation of the GABA_A 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. 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.

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 Savant syndrome ( , ) is a phenomenon where someone demonstrates exceptional aptitude in one domain, such as art or mathematics, despite significant social or intellectual impairment. Those with the condition generally have a neurodevel ...

skills accompanying such disorders. 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. These mice also exhibit changes to the

vestibular system The vestibular system, in vertebrates, is a sensory system that creates the sense of balance and spatial orientation for the purpose of coordinating motor coordination, movement with balance. Together with the cochlea, a part of the auditory sys ...

within the ear, resulting in poor swimming skills, difficulty in walking on grid floors, and are found to run in circles erratically.

Angelman syndrome

Deletion of the GABRB3 gene results in Angelman syndrome in humans, depending on the parental origin of the deletion. 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.

Nonsyndromic Orofacial Clefting

There is a strong association between GABRB3 expression levels and proper

palate The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly sep ...

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 A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

into the mouse genome, making the Gabrb3 gene primarily responsible for cleft palate formation.

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. 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. 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. The Gabrb3 gene deficient mouse has been proposed as a model of autism spectrum disorder. 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. There is an unknown association between autism and the 155CA-2 locus, located within an intron in GABRB3.

Epilepsy/Childhood absence epilepsy

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

References

External links

* * {{Ligand-gated ion channels Ion channels Genetics of autism