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

Abstract

Objective: γ-Aminobutyric acid (GABA) A -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA A -receptorrelated disorders as a whole and seek possible genotype-phenotype correlations. Methods:We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA A -receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. Results:We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA A -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.Significance: GABA A -receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics. K E Y W O R D Schannelopathy, developmental and epileptic encephalopathy, GABA A receptor, genetic generalized epilepsy Key points• γ-Aminobutyric acid (GABA) A -receptor subunit variants lead to a fever-related epilepsy, a generalized epilepsy, or a developmental and epileptic encephalopathy • Phenotype was not associated with a given gene, but with the location of variants within the protein • Variants of the transmembrane domain are significantly more severe than other variants in our cohort and in 402 published cases.

Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants

“…In this study, we focus on the α1 subunit of GABA A receptors: a growing number of clinical variants ( > 200 variants according to www.clinvar.com, including missense, frameshift, and nonsense variants) have been identified in this subunit to be associated with genetic epilepsy covering a broad phenotypic spectrum 6,7,35,36 . These variations are distributed throughout the protein sequence in the NTD, the transmembrane domain (TM1, TM2, TM3, and TM4), and the loops connecting TM helices (Fig.…”

Precision medicine: Vinpocetine as a potential treatment for GABRG2‐related epilepsy

“…GABRG2 pathogenic variants are associated with simple febrile seizures (FS) and genetic epilepsy syndromes including childhood absence epilepsy (CAE), generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (DS), and developmental and epileptic encephalopathy (DEE). [2][3][4] The penetrance and phenotype of GABRG2 variants may vary, even within the same family. 2 Missense, nonsense, and frameshift variants, and splice site and gene deletion have been described.…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…As mentioned previously, inhibitory neurotransmission dysfunction in developmental behavioural and psychiatric disorders is well-established [ 36 ]. Clinical studies and animal models have shown that dysfunction may involve reduced levels of inhibitory neurotransmitters in cerebro-spinal fluid [ 330 , 331 ], the GABA and/or glycine receptors (reduced expression levels or loss-of-function mutations) [ 332 , 333 , 334 ], reduced inhibitory circuit inputs [ 335 , 336 , 337 ] and altered chloride channel expression [ 338 , 339 , 340 , 341 ]. In cerebral palsy, there is evidence of decreased GABA-A receptors in the cerebrospinal fluid [ 342 ] and reduced GABA receptor expression in the brainstem, but not the cortex (a further nail in the coffin of the cerebral primacy of the aetiology) [ 343 ], deficits in reciprocal inhibition [ 344 , 345 , 346 ], suggestions of reduced cortical inhibition [ 347 , 348 ] and a relationship between the of loss of inhibition and the degree of physical motor dysfunction [ 349 ].…”