GABRA1

Official Full Name

gamma-aminobutyric acid type A receptor subunit alpha5

Organism

Homo sapiens

GeneID

2558

Background

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

Synonyms

DEE79; EIEE79;

Bio Chemical Class

Ligand-gated ion channel

Protein Sequence

MDNGMFSGFIMIKNLLLFCISMNLSSHFGFSQMPTSSVKDETNDNITIFTRILDGLLDGYDNRLRPGLGERITQVRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRFKGPMQRLPLNNLLASKIWTPDTFFHNGKKSIAHNMTTPNKLLRLEDDGTLLYTMRLTISAECPMQLEDFPMDAHACPLKFGSYAYPNSEVVYVWTNGSTKSVVVAEDGSRLNQYHLMGQTVGTENISTSTGEYTIMTAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISARNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKKALEAAKIKKKREVILNKSTNAFTTGKMSHPPNIPKEQTPAGTSNTTSVSVKPSEEKTSESKKTYNSISKIDKMSRIVFPVLFGTFNLVYWATYLNREPVIKGAASPK

Open

Disease

Adaptive immunity immunodeficiency, Alzheimer disease, Autism spectrum disorder, Indeterminate colitis, Intentional self-harm, Mild neurocognitive disorder, Postoperative inflammation, Sex development malformative disorder

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

GABRA1 is a member of the family of subunits that make up GABAAR, and its encoding gene is located on chromosome 5q34, encoding the α1 subunit of GABAAR, which consists of 10 exons and is responsible for encoding 474 amino acids.

GABAAR, which consists of the GABRA1 subunit involved, is an important inhibitory receptor in the nervous system. Since the concentration of chloride ions in most neuronal cells is low compared to the extracellular ones, when GABAAR is activated by GABA, the receptor channel opens and the chloride ions flow into the cell, which hyperpolarizes the neuronal cell membrane, raises the threshold of generating an action potential, and reduces the neural excitability; whereas, when the GABAAR dysfunction leads to blockage of GABA transmission and increased neuronal cell excitability, ultimately leading to epilepsy.

This figure illustrates the key action sites of antiseizure medications. Figure 1. The major sites of action of antiseizure medications. (Feng Y, et al., 2022)

The pathogenic mechanism after mutation of this gene is mainly twofold:

(1) GABRA1 gene mutation can lead to chloride channel dysfunction by affecting the binding of the neurotransmitter GABA to the receptor, which will prevent the generation of effective inhibitory postsynaptic potentials, thus increasing neuronal cell excitability and leading to epileptiform discharges;

(2) GABRA1 gene variants can cause the loss of function of GABAAR, and when its function is lost it will not be able to complete integration at the cell membrane properly, thus affecting the postsynaptic inhibition function mediated by it, leading to epileptiform discharges.

Among the available reported cases, hereditary GABRA1 gene mutations account for the minority, and de novo mutations predominate. The phenotypic similarity of patients carrying the same GABRA1 variant within the same family line is suggestive in evaluating the prognosis of children with a parental origin of the variant, as well as clarifying the direction of early treatment of such children. In terms of age of onset, most of the children had onset in infancy.

GABRA1 variant-associated epileptic seizures have various seizure forms, including focal seizures, convulsive seizures, generalized tonic-clonic seizures, and myoclonic seizures, with focal seizures and generalized tonic-clonic seizures being the most common. In terms of seizure triggers, some children may have seizures induced by fever and flash stimuli, and the induced seizures are often in the form of myoclonic and tonic-clonic seizures. Among these children, there are mild febrile seizure-plus (FS+) and more severe epileptic encephalopathy.

The majority of children have poor intellectual, motor, and language development, while a few may have normal development in these areas. Some children may show only severe developmental delay without significant seizures.

On EEG, children with GABRA1 variant-associated epileptic encephalopathy may show peak dysrhythmias or burst inhibition. In reported cases, GABRA1 variant-associated epilepsy may present as juvenile myoclonic epilepsy (JME), childhood absence epilepsy, infantile spasms, early-onset epileptic encephalopathy, Dravet syndrome, and many other epilepsy syndromes.

Therapeutically, in terms of pathogenesis and mechanism of drug action, children with GABRA1 variant-associated genetic epilepsy can be considered for this type of drug therapy because valproic acid and aminoglutethimide are inhibitors of GABA transaminase, which inhibit GABA catabolism, and retain a higher concentration of GABA in the synaptic gap, which in turn reduces seizures.

In the literature, most of the children are well-treated with antilevetiracetam and valproic acid, and a few need a combination of drugs to control their seizures.

Oxcarbazepine has been reported to exacerbate seizures in some children with GABRA1 variant-associated hereditary epilepsy, but the mechanism of action is unclear, a finding that suggests that oxcarbazepine should be avoided when children are diagnosed with, or being considered for, a diagnosis of GABRA1 variant-associated hereditary epilepsy.

References:

Maillard PY, Baer S, Schaefer É, et al. Molecular and clinical descriptions of patients with GABA_A receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation. Epilepsia. 2022;63(10):2519-2533.
Feng Y, Wei ZH, Liu C, et al. Genetic variations in GABA metabolism and epilepsy. Seizure. 2022;101:22-29.

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