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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

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

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

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

genome In the fields of molecular biology and genetics, 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 ge ...

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 sequen ...

s within its

coding region The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to no ...

. Due to

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

, 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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

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. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

cerebellum The cerebellum (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 or even larger. In humans, the cerebel ...

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

olivary body In anatomy, the olivary bodies or simply olives (Latin ''oliva'' and ''olivae'', singular and plural, respectively) are a pair of prominent oval structures in the medulla oblongata, the lower portion of the brainstem. They contain the olivary nuc ...

and

piriform cortex The piriform cortex, or pyriform cortex, is a region in the brain, part of the rhinencephalon situated in the cerebrum. The function of the piriform cortex relates to the sense of smell. Structure The piriform cortex is part of the rhinencepha ...

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 disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...

s and syndromes such as

Angelman syndrome Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...

, Prader-Willi syndrome, nonsyndromic orofacial clefts,

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

and

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

. 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 met ...

and

etomidate Etomidate (USAN, INN, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardiove ...

are mediated through GABBR3

positive allosteric modulation In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

Gene

The GABRB3 gene is located on the long arm of

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

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

gene cluster A gene family is a set of homologous genes within one organism. A gene cluster is a group of two or more genes found within an organism's DNA that encode similar polypeptides, or proteins, which collectively share a generalized function and are o ...

, with two other genes,

GABRG3 GABAA receptor-γ3, also known as GABRG3, is a protein which in humans is encoded by the ''GABRG3'' gene. Function GABRG3 is a subunit of the GABAA receptor for the neurotransmitter gamma-Aminobutyric acid ( GABA). Association with alcoholism ...

and

GABRA5 Gamma-aminobutyric acid (GABA) A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the ''GABRA5'' gene. Function gamma-aminobutyric acid, GABA is the major inhibitory neurotransmitter in the mammalian brain where ...

. 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 peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

Alternatively spliced Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

transcript variants encoding

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

s 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., gene. ...

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

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

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 () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

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 Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

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 synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

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

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

s. 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. Mo ...

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. Substitution of protein from DNA mutations Missense m ...

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

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

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 the ordered arrangement of atoms, ions or molecules in a crystal, crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pat ...

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 cell differentiation, differentiation of both developing and mature neurons. Most ...

, 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 The mouse brain refers to the brain of Mus musculus. Various brain atlases exist. For reasons of reproducibility, genetically characterized, stable strains like C57BL/6 were chosen to produce high-resolution images and databases. Well known onli ...

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 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...

. 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 rare condition in which someone with significant mental disabilities demonstrates certain abilities far in excess of average. The skills that savants excel at are generally related to memory. This may include rapid calcu ...

skills accompanying such disorders. In mice, the

knockout mutation A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene k ...

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 movement with balance. Together with the cochlea, a part of the auditory system, it constitutes ...

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 sepa ...

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 Causes of autism