Wednesday, October 26, 2022

GABRB3 mutations

Inspired by a patient

Mishra A, Prabha PK, Singla R, Kaur G, Sharma AR, Joshi R, Suroy B, Medhi B. Epigenetic Interface of Autism Spectrum Disorders (ASDs): Implications of Chromosome 15q11-q13 Segment. ACS Chem Neurosci. 2022 Jun 15;13(12):1684-1696. doi: 10.1021/acschemneuro.2c00060. Epub 2022 May 28. PMID: 35635007.


Autism spectrum disorders (ASDs) are multifactorial in nature and include both genetic and environmental factors. The increasing evidence advocates an important role of epigenetics in ASD etiology. One of the most common forms of epigenetic changes observed in the case of neurodevelopmental disorders is imprinting which is tightly regulated by developmental and tissue-specific mechanisms. Interestingly, many of these disorders that demonstrate autism-like phenotypes at varying degrees have found involvement of chromosome 15q11-q13 segment. Numerous studies demonstrate occurrence of ASD in the presence of chromosomal abnormalities located mainly in Chr15q11-q13 region. Several plausible candidate genes associated with ASD are in this chromosomal segment, including gamma aminobutyric acid A (GABAA) receptor genes GABRB3, GABRA5 and GABRG3, UBE3A, ATP 10A, MKRN3, ZNF, MAGEL2, Necdin (NDN), and SNRPN. The main objective of this review is to highlight the contribution of epigenetic modulations in chromosome 15q11-q13 segment toward the genetic etiology and pathophysiology of ASD. The present review reports the abnormalities in epigenetic regulation on genes and genomic regions located on chromosome 15 in relation to either syndromic (15q11-q13 maternal duplication) or nonsyndromic forms of ASD. Furthermore, studies reviewed in this article demonstrate conditions in which epigenetic dysregulation has been found to be a pathological factor for ASD development, thereby supporting a role for epigenetics in the multifactorial etiologies of ASD. Also, on the basis of the evidence found so far, we strongly emphasize the need to develop future therapeutic strategies as well as screening procedures for ASD that target mechanisms involving genes located on the chromosomal 15q11-q13 segment.

Feng Y, Wei ZH, Liu C, Li GY, Qiao XZ, Gan YJ, Zhang CC, Deng YC. Genetic variations in GABA metabolism and epilepsy. Seizure. 2022 Oct;101:22-29. doi: 10.1016/j.seizure.2022.07.007. Epub 2022 Jul 15. PMID: 35850019.


Epilepsy is a paroxysmal brain disorder that results from an imbalance between neuronal excitation and inhibition. Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain and plays an important role in the occurrence and development of epilepsy. Abnormalities in all aspects of GABA metabolism, including GABA synthesis, transport, genes encoding GABA receptors, and GABA inactivation, may lead to epilepsy. GABRA1, GABRA2, GABRA5, GABRB1, GABRB2, GABRB3, GABRG2 and GABBR2 are genes that encode GABA receptors and are commonly associated with epilepsy. Mutations of these genes lead to a variety of epilepsy syndromes with different clinical phenotypes, primarily by down regulating receptor expression and reducing the amplitude of GABA-evoked potentials. GABA is metabolized by GABA transaminase and succinate semi aldehyde dehydrogenase, which are encoded by the ABAT and ALDH5A1 genes, respectively. Mutations of these genes result in symptoms related to deficiency of GABA transaminase and succinate semi aldehyde dehydrogenase, such as epilepsy and cognitive impairment. Most of the variation in genes associated with GABA metabolism are accompanied by developmental disorders. This review focuses on advances in understanding the relationship between genetic variation in GABA metabolism and epilepsy to establish a basis for the accurate diagnosis and treatment of epilepsy.

Absalom NL, Liao VWY, Johannesen KMH, Gardella E, Jacobs J, Lesca G, Gokce-Samar Z, Arzimanoglou A, Zeidler S, Striano P, Meyer P, Benkel-Herrenbrueck I, Mero IL, Rummel J, Chebib M, Møller RS, Ahring PK. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies. Nat Commun. 2022 Apr 5;13(1):1822. doi: 10.1038/s41467-022-29280-x. PMID: 35383156; PMCID: PMC8983652.


Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, Vaher U, Borggraefe I, Talvik I, Talvik T, Kluger G, Francois LL, Lesca G, de Bellescize J, Blichfeldt S, Chatron N, Holert N, Jacobs J, Swinkels M, Betzler C, Syrbe S, Nikanorova M, Myers CT, Larsen LH, Vejzovic S, Pendziwiat M, von Spiczak S, Hopkins S, Dubbs H, Mang Y, Mukhin K, Holthausen H, van Gassen KL, Dahl HA, Tommerup N, Mefford HC, Rubboli G, Guerrini R, Lemke JR, Lerche H, Muhle H, Maljevic S. Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. Neurology. 2017 Jan 31;88(5):483-492. doi: 10.1212/WNL.0000000000003565. Epub 2017 Jan 4. PMID: 28053010; PMCID: PMC5278942.


Objective: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes.

Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs.

Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β3, together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations.

Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.

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