GABRA5

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

The GABRA5 gene is a critical component in the mammalian brain's inhibitory neurotransmitter system. This 2,553 base pair gene, found on chromosome 15q12, has 11 exons and encodes the α5 subunit of the GABAA receptor. In the central nervous system, GABAA receptors are ligand-gated chloride channels that control rapid inhibitory neurotransmission. Distinctive expression patterns of the gene across brain areas reveal especially high levels in the hippocampus, olfactory bulb, cerebral cortex, amygdala, and basal ganglia, suggesting its vital position in cognitive functioning and emotional processing. Recent research has shown that GABRA5 expression is developmentally controlled, peaking in early brain development, especially during times of synaptic plasticity and circuit building.

Figure 1. α5 subunit-containing GABA type A receptor (α5 GABAAR) structure and subunit topology. (Jacob TC. 2019)

Clinical Manifestations of DEE79

Developmental and Epileptic Encephalopathy 79 (DEE79), first identified in 2018, is caused by mutations in the GABRA5 gene and follows an autosomal dominant inheritance pattern. The condition typically manifests between 2-4 months of age with various seizure types including myoclonic, atonic, and generalized tonic-clonic seizures, along with oropharyngeal automatism and wandering focal seizures. Patients consistently show severe cognitive and motor impairments, with most lacking language development. Neurological examination often reveals hypo dystonia, secondary microcephaly, limb spasms, and autism spectrum features. Sleep disturbances are commonly reported, with irregular sleep-wake patterns and frequent nocturnal seizures. Early developmental milestones are typically delayed or absent, and patients often show feeding difficulties and gastrointestinal issues. Behavioral abnormalities, including irritability, self-injurious behaviors, and reduced social interaction, are frequently observed.

Diagnostic Features

Diagnostic imaging and electrical studies reveal consistent abnormalities. EEG findings show extensive background slow waves, multifocal sharp-wave emissions, and peak irregularities. Including burst-suppression patterns during sleep in some situations, video-EEG monitoring has identified certain patterns linked to various seizure types. Usually showing corpus callosum thinning, brain atrophy, hypomyelination, and lower white matter volume, MRI scans suggest major structural effects of the disease. Affected people have been shown to have changed connection patterns, especially in networks containing the hippocampus and temporal lobe areas, using advanced neuroimaging technologies like as functional MRI and diffusion tensor imaging.

Genetic Variants and Molecular Mechanisms

Three harmful missense mutations in the GABRA5 gene have been found: p.Val294Phe (seen in two instances), p.Val294Leu, and p.Ser413Phe. While Ser413 is at the intracellular C-terminal, the Val294 mutations influence the transmembrane region of the protein. In vitro experiments have shown that these variations affect GABAA receptor surface expression and permeability differently, hence causing lower neuronal inhibition and general malfunction. Cell model electrophysiological research has shown changed channel kinetics and lower chloride conductivity. Recent molecular dynamics simulations have shown how these mutations influence receptor shape and function. Animal models with comparable mutations exhibit similar symptoms to human patients, including seizures and cognitive deficits.

Treatment Strategies and Challenges

Treatment methods for DEE79 are still hotly debated as different ones call for different choices of antiepileptic medications. Particularly phenobarbital, one method counsels against utilizing positive allosteric modulators of GABA receptors in situations with reduced GABA sensitivity. A different approach calls for mixing many antiepileptic medications, particularly those influencing GABA metabolism, like clobazam. In some situations, ketogenic diet treatment has been promising, resulting in better seizure control and cognitive performance. Under research new therapeutic methods include gene therapy plans, antisense oligonucleotides, and targeted molecular treatments. To maximize developmental results, early intervention with thorough rehabilitation programs—including physical therapy, occupational therapy, and speech therapy—is advised.

Prognosis and Future Directions

The prognosis for DEE79 remains poor, characterized by drug-resistant seizures and severe developmental impacts. Studies on long-term follow-up have shown that most individuals need lifetime care and assistance. Targeted therapy development, genotype-phenotype connections, and best medication combination discovery are all subjects of ongoing study. Recent developments in precision medicine techniques, such as pharmacogenomics and tailored medication selection depending on certain genetic variations, offer promise. International consortiums are working to establish patient registries and natural history studies to better understand disease progression and identify potential therapeutic windows. The study of GABRA5-related epilepsy continues to provide insights into GABAergic system dysfunction and potential therapeutic approaches for both this condition and related disorders. Emerging technologies, including CRISPR-based gene editing and novel drug delivery systems, offer hope for more effective treatments in the future.

References:

Luscher B, Maguire JL, Rudolph U, et al. GABAA receptors as targets for treating affective and cognitive symptoms of depression. Trends Pharmacol Sci. 2023;44(9):586-600.
Neklyudova A, Smirnov K, Rebreikina A, et al. Electrophysiological and Behavioral Evidence for Hyper- and Hyposensitivity in Rare Genetic Syndromes Associated with Autism. Genes (Basel). 2022;13(4):671.
Jacob TC. Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors. Front Mol Neurosci. 2019;12:179.

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