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The GABRA1 gene encodes the α1 subunit of the GABAA receptor, a pentameric chloride channel critical for inhibitory neurotransmission. Heterozygous de novo variants in GABRA1 have been repeatedly identified in patients with developmental and epileptic encephalopathy (DEE), implicating both loss-of-function (LoF) and gain-of-function (GoF) mechanisms in disease pathogenesis. Detailed genotype–phenotype correlations reveal that variants in the extracellular domain often lead to fever-sensitive epilepsies with favorable outcomes, while variants in transmembrane helices or pore regions associate with more severe early-onset DEE. Functional studies in Xenopus oocytes, mammalian cells, and zebrafish models consistently demonstrate aberrant channel gating, altered GABA sensitivity, reduced surface trafficking, and disrupted inhibitory network development in vivo.
In trio‐based exome sequencing of six unrelated DEE patients, three missense variants (c.247C>A (p.His83Asn), c.619G>T (p.Val207Phe), c.640C>T (p.Arg214Cys)) and one frameshift (c.1357_1358del (p.Thr453HisfsTer47)) were identified; p.Arg214Cys recurred in three severe DEE cases (PMID:38269327). A separate cohort of 11 patients with paralogous M1 proline variants, including c.778C>T (p.Pro260Ser) and c.778C>G (p.Pro260Leu), all presented with DEE and global developmental delay (PMID:39642202). Additional de novo GABRA1 mutations were reported in six Ohtahara/West syndrome patients (PMID:26918889) and four Dravet syndrome cases (PMID:24623842), totaling over 30 unrelated probands with DEE.
Most pathogenic GABRA1 variants are missense, with recurrent hotspots at p.Arg112 and p.Pro260, complemented by frameshift and splice variants causing truncated α1 subunits. None of these variants are observed in gnomAD. Segregation is predominantly de novo, with no evidence of inherited familial clustering. Population-specific founder alleles have not been described for DEE. The overall inheritance pattern is autosomal dominant with de novo occurrence, consistent with haploinsufficiency or dominant-negative effects.
Electrophysiological assays reveal that LoF α1 variants produce diminished GABA-evoked currents, accelerated deactivation, and reduced receptor surface expression, while GoF variants increase GABA sensitivity by 3- to 23-fold, sometimes accompanied by enhanced desensitization (PMID:39642202). A gabra1−/− zebrafish model recapitulates seizure-like hypermotility, altered inhibitory synapse development, and transcriptomic disruptions in neurodevelopmental pathways (PMID:30324621). Rescue experiments with human wild-type α1 restore phenotypes, whereas pathogenic variants fail to do so.
Mechanistically, DEE-associated GABRA1 variants impair early inhibitory network wiring and chloride conductance, leading to hyperexcitability. Both LoF and GoF mutations converge on disrupted excitation–inhibition balance, as demonstrated by cellular models and animal systems. Pharmacological chaperones and subtype-selective modulators can partially restore proteostasis and channel function, highlighting avenues for precision therapy. No studies to date substantively refute the GABRA1–DEE association.
Collectively, extensive de novo genetic findings, concordant functional evidence, and animal model data support a Strong clinical validity for GABRA1 in DEE. GABRA1 testing is recommended in early-onset epileptic encephalopathy workups, with variant-specific functional assays guiding prognosis and therapeutic strategies.
Gene–Disease AssociationStrongOver 30 unrelated probands with de novo GABRA1 variants across multiple studies, recurrent hotspots, and concordant functional data Genetic EvidenceStrongDe novo missense and frameshift variants in ~30 DEE probands, including recurrent p.Arg214Cys; reached ClinGen genetic cap Functional EvidenceModerateMultiple electrophysiological and zebrafish model studies demonstrating LoF/GoF mechanisms and rescue experiments |