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. 2014 Nov;164A(11):2914-21.
doi: 10.1002/ajmg.a.36714. Epub 2014 Aug 13.

A novel variant in GABRB2 associated with intellectual disability and epilepsy

Siddharth Srivastava  1 , Julie Cohen, Jonathan Pevsner, Swaroop Aradhya, Dianalee McKnight, Elizabeth Butler, Michael Johnston, Ali Fatemi
Affiliations

A novel variant in GABRB2 associated with intellectual disability and epilepsy

Siddharth Srivastava et al. Am J Med Genet A. 2014 Nov.

Abstract

The γ-aminobutyric acid type A (GABAA ) receptor is one of the three main classes of receptors activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Mutations in genes encoding various subunits of this receptor (GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRG1, GABRG2, GABRG3, and GABRD) are implicated in a number of neurological and developmental disorders, including epilepsy and autism. To date, no human genetics studies have implicated mutations in GABRB2, encoding the β2 subunit of the GABAA receptor, with neurodevelopmental disorders. Here we present a 12-year-old girl with intellectual disability and epilepsy, who was discovered by whole exome sequencing to have a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T>C; p.M79T). This variant is likely pathogenic, based on in silico analyses, as well as the fact that it results in the non-conservative substitution of a non-polar amino acid with a polar amino acid at a position that is evolutionarily conserved across multiple species. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction.

Keywords: GABAA receptor; GABRB2; epilepsy; intellectual disability.

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Conflict of interest statement

CONFLICTS OF INTEREST

Swaroop Aradhya, Dianalee McKnight, and Elizabeth Butler are paid employees of GeneDx Laboratory.

Figures

Figure 1
Figure 1
Sample EEG recording from the proband.
Figure 2
Figure 2
Multiple sequence alignment of human GABRB2 with related peptides. a) Multiple sequence alignment of vertebrate GABRB2 homologs, with focus on the region surrounding position 79 of human GABRB2. b) Multiple sequence alignment of human GABRB2 with the human β1 subunit (GABRB1) and β3 subunit (GABRB3) of the GABAA receptor, with focus on the region surrounding position 79 of human GABRB2. The arrow indicates all the conserved residues at position 79 of human GABRB2. An asterisk (‘*’) denotes a position where residues are conserved. A period (‘.’) denotes a position where there is conservation between groups of amino acids with weakly similar properties. A colon (‘:’) denotes a position where there is conservation between groups of amino acids with strongly similar properties. The National Center for Biotechnology Information (NCBI) Reference Sequence accession number for each protein is indicated in parentheses.
Figure 3
Figure 3
Structural comparison of human GABRB2 with the homopentameric C. elegans glutamategated chloride channel GluClα. a) Alignment of human GABRB2 to each subunit of GluClα (E = 1e-71, 42% identities, 62% positives). The arrow indicates position 79 of human GABRB2. b) Two 3D representations of GluClα. The first (left) is looking parallel to the membrane. The second (right) is looking down the pore from the intracellular side toward the extracellular side. The intracellular (“In”) and extracellular (“Out”) sides are indicated. The red circle and arrow indicates the residue (M47) within the β2 loop of each subunit of GluClα, corresponding to M79 in human GABRB2 (note that this residue is not always visible within each subunit depending on the angle of the 3D view).
Figure 4
Figure 4
Schematic of the GABAA receptor. a) Transmembrane topology of each receptor subunit. Each subunit has a large extracellular N-terminal binding domain, four TM segments, and an extracellular Cterminal end. b) Assembly of the receptor from different classes of subunits. The receptor is composed of two α subunits, two β subunits, and one additional γ subunit (which can be replaced by a δ, ε, θ, or π subunit). The binding site for GABA is located at the interface between the α and β subunits. A binding site for benzodiazepines (BZs) is located at the interface between the α and γ subunits. Ligand binding activates the receptor, which then becomes permeable to chloride (Cl-) anions. Figure is reprinted with permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience (Jacob et al., 2008), copyright 2008.
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References

    1. Audenaert D, Schwartz E, Claeys KG, Claes L, Deprez L, Suls A, Van Dyck T, Lagae L, Van Broeckhoven C, Macdonald RL, De Jonghe P. A novel GABRG2 mutation associated with febrile seizures. Neurology. 2006;67:687–690. - PubMed
    1. Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme JF, Baulac M, Brice A, Bruzzone R, LeGuern E. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet. 2001;28:46–48. - PubMed
    1. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci. 2002;22:5572–5580. - PMC - PubMed
    1. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire J-M, Carmant L, Verner A, Lu W-Y, Wang YT, Rouleau GA. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–189. - PubMed
    1. Dibbens LM, Feng H-J, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004;13:1315–1319. - PubMed

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