Chapter 3 - Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy

https://doi.org/10.1016/B978-0-444-63326-2.00003-XGet rights and content

Abstract

The γ-aminobutyric acid receptor type A (GABAA receptor) is a ligand-gated chloride channel that mediates major inhibitory functions in the central nervous system. GABAA receptors function mainly as pentamers containing α, β, and either γ or δ subunits. A number of antiepileptic drugs have agonistic effects on GABAA receptors. Hence, dysfunctions of GABAA receptors have been postulated to play important roles in the etiology of epilepsy. In fact, mutations or genetic variations of the genes encoding the α1, α6, β2, β3, γ2, or δ subunits (GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and GABRD, respectively) have been associated with human epilepsy, both with and without febrile seizures. Epilepsy resulting from mutations is commonly one of following, genetic (idiopathic) generalized epilepsy (e.g., juvenile myoclonic epilepsy), childhood absence epilepsy, genetic epilepsy with febrile seizures, or Dravet syndrome. Recently, mutations of GABRA1, GABRB2, and GABRB3 were associated with infantile spasms and Lennox–Gastaut syndrome. These mutations compromise hyperpolarization through GABAA receptors, which is believed to cause seizures. Interestingly, most of the insufficiencies are not caused by receptor gating abnormalities, but by complex mechanisms, including endoplasmic reticulum (ER)-associated degradation, nonsense-mediated mRNA decay, intracellular trafficking defects, and ER stress. Thus, GABAA receptor subunit mutations are now thought to participate in the pathomechanisms of epilepsy, and an improved understanding of these mutations should facilitate our understanding of epilepsy and the development of new therapies.

Section snippets

GABAA Receptors

The γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) are ligand-gated chloride (Cl) channels that mediate major inhibitory functions in the central nervous system (CNS). Many antiepileptic drugs (AEDs) are GABAA receptor agonists, whereas GABAA receptor antagonists can be strong convulsants. Hence, GABAA receptors have been postulated to play a key role in the pathogenesis of epilepsy. In fact, mutations and variations in the genes encoding GABAA receptor subunits have been

Mutations and Genetic Variations of the GABAA Receptor

Mutations and genetic variations of GABAA receptors have been associated with epilepsy (Table 1). However, only a limited number of epilepsy types result from such mutations, which are not necessarily the direct cause of epilepsy (Kim et al., 2012, Ma et al., 2006a, Ma et al., 2006b, Xiumin et al., 2007). Nevertheless, the list of GABAA receptor mutations associated with epilepsy is expected to grow in the future. Furthermore, these GABAA receptor mutations have revealed new aspects of the

Mutations of the α Subunit

The α subunit is the requisite subunit for GABAA receptors, as it is the GABA binding site that initiates GABA-evoked potentials and forms the benzodiazepine binding site with the γ subunit. Several mutations of the genes encoding the α1 (GABRA1) and α6 (GABRA6) subunits have been identified in autosomal dominant juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), and infantile spasms (ISs).

Mutations of the β Subunit

The β subunit is considered a major subunit of the GABAA receptor and is expressed predominantly in the human brain. The β2 subtype is considered the major constituent of the GABAA receptor in the adult brain, both quantitatively and spatially. In contrast, the β3 subtype is considered a major constituent in the developing brain, which indicates an important role in the developing brain, and hence in the etiology of childhood CNS disorders (Brooks-Kayal and Pritchett, 1993). A previous

Mutations of the γ Subunit

At present, more than a dozen mutations of GABRG2, the gene that encodes the γ2 subunit, have been associated with idiopathic epilepsy; most of these mutations are associated with FS. This indicates that the γ2 subunit plays an important role in the pathomechanisms of epilepsy. In fact, the γ2 subunit is considered one of the major receptor components that allow GABAA receptors to modulate phasic or synaptic transmission (Farrant and Nusser, 2005, Olsen and Sieghart, 2008, Sieghart and Sperk,

Mutations of the δ Subunit

The δ subunit is an important constituent of the GABAA receptors mediating tonic inhibition in neurons. This is in contrast to the γ subunits that are a major component of the receptors mediating phasic inhibition (Bai et al., 2001, Saxena and MacDonald, 1994, Stell et al., 2003, Wei et al., 2003). At present, three genetic variations (E177A, R220C, and R220H) of GABRD, the gene encoding δ subunit, have been associated with epilepsy in a cohort study with 72 unrelated GGE, 65 unrelated GEFS +,

Therapeutic Implications of GABAA Receptor Mutations

Mutations of GABAA receptor subunits have been associated with GGE and FS. Furthermore, there is evidence that deficient GABAergic neurons play a crucial role in the development of epilepsy. Thus, GABA receptors are likely key players in the pathomechanisms of epilepsy. Keeping this in mind, GABAA receptors should be considered for their potential in therapeutic intervention.

Besides the mutant GABAA receptors described above, one line of evidence indicates that GABAA receptors and GABAergic

Conclusions

The GABAA receptors are one type of ion channels with genetic mutations or variations that underlie epilepsy. Contrary to the mutations of other ion channels that affect channel functions, mutations of GABAA receptor subunits show more complex pathomechanisms of epilepsy. Thus, the pathomechanisms resulting from such mutations are closely associated with cell mechanisms such as ERAD, NMD, intracellular trafficking defects, and ER stress. Thus, mutations of GABAA receptor subunits have revealed

Acknowledgment

The author thanks Dr. Jing-Qiong Kang, Vanderbilt University Medical Center, and Dr. Chritoph Lossin, Department of Neurology, School of Medicine UC Davis, for their careful and critical reading of the manuscript. This work was supported by Grant-in-Aid for Scientific Research (A) (24249060); Grant-in-Aid for Challenging Exploratory Research (25670481); Bilateral Joint Research Projects (S. H.) from Japan Society for the Promotion of Science; Grants for Scientific Research on Innovative Areas

References (122)

  • T.G. Hales et al.

    The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors

    Mol. Cell. Neurosci.

    (2005)
  • T.G. Hales et al.

    An asymmetric contribution to gamma-aminobutyric type A receptor function of a conserved lysine within TM2-3 of α1, β2, and γ2 subunits

    J. Biol. Chem.

    (2006)
  • L.A. Harkin et al.

    Truncation of the GABA(A)-receptor γ2 subunit in a family with generalized epilepsy with febrile seizures plus

    Am. J. Hum. Genet.

    (2002)
  • S. Hirose et al.

    Are some idiopathic epilepsies disorders of ion channels? A working hypothesis

    Epilepsy Res.

    (2000)
  • S. Hirose et al.

    Genetic abnormalities underlying familial epilepsy syndromes

    Brain Dev.

    (2002)
  • S. Hirose et al.

    The genetics of febrile seizures and related epilepsy syndromes

    Brain Dev.

    (2003)
  • X. Huang et al.

    The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through

    Neurobiol. Dis.

    (2012)
  • A. Ishii et al.

    Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy

    Epilepsy Res.

    (2014)
  • M. Ito et al.

    Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na +)-channel α1 subunit gene, SCN1A

    Epilepsy Res.

    (2002)
  • A.J. Johnston et al.

    A novel GABRG2 mutation, p.R136*, in a family with GEFS + and extended phenotypes

    Neurobiol. Dis.

    (2014)
  • J.Q. Kang et al.

    Making sense of nonsense GABA(A) receptor mutations associated with genetic epilepsies

    Trends Mol. Med.

    (2009)
  • E.F. Kirkness et al.

    A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor β3 subunit (GABRB3)

    J. Biol. Chem.

    (1993)
  • J.E. Kralic et al.

    GABA(A) receptor α-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem

    Neuropharmacology

    (2002)
  • K.P. Lenzen et al.

    Association analysis of the Arg220His variation of the human gene encoding the GABA δ subunit with idiopathic generalized epilepsy

    Epilepsy Res.

    (2005)
  • S. Ma et al.

    Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures

    Neurosci. Lett.

    (2006)
  • S. Ma et al.

    Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy

    Epilepsy Res.

    (2006)
  • R.L. MacDonald et al.

    GABA(A) receptor epilepsy mutations

    Biochem. Pharmacol.

    (2004)
  • K. Migita et al.

    Properties of a novel GABAA receptor γ2 subunit mutation associated with seizures

    J. Pharmacol. Sci.

    (2013)
  • A.S. Allen et al.

    De novo mutations in epileptic encephalopathies

    Nature

    (2013)
  • F.M. Arain et al.

    Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor alpha1 subunit

    Epilepsia

    (2012)
  • D. Audenaert et al.

    A novel GABRG2 mutation associated with febrile seizures

    Neurology

    (2006)
  • D. Bai et al.

    Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons

    Mol. Pharmacol.

    (2001)
  • S. Baulac et al.

    First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene

    Nat. Genet.

    (2001)
  • A.T. Berg et al.

    Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009

    Epilepsia

    (2010)
  • M.T. Bianchi et al.

    Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans

    J. Neurosci.

    (2002)
  • W. Bouthour et al.

    A human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABAA receptors

    Cereb. Cortex

    (2012)
  • D.N. Bowser et al.

    Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [γ2(R43Q)] found in human epilepsy

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • A.R. Brooks-Kayal et al.

    Developmental changes in human gamma-aminobutyric acid A receptor subunit composition

    Ann. Neurol.

    (1993)
  • G.L. Carvill et al.

    Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

    Nat. Genet.

    (2013)
  • D. Chandra et al.

    GABAA receptor gamma 2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines

    BMC Neurosci.

    (2005)
  • C. Chen et al.

    Mice lacking sodium channel β1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture

    J. Neurosci.

    (2004)
  • C. Chiu et al.

    Developmental impact of a familial GABAA receptor epilepsy mutation

    Ann. Neurol.

    (2008)
  • E.H. Cook et al.

    Autism or atypical autism in maternally but not paternally derived proximal 15q duplication

    Am. J. Hum. Genet.

    (1997)
  • D.W. Cope et al.

    Enhanced tonic GABAA inhibition in typical absence epilepsy

    Nat. Med.

    (2009)
  • P. Cossette et al.

    Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

    Nat. Genet.

    (2002)
  • P. Cossette et al.

    Mutated GABAA receptor subunits in idiopathic generalized epilepsy

  • F. Crestani et al.

    Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues

    Nat. Neurosci.

    (1999)
  • R.J. Delahanty et al.

    Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism

    Mol. Psychiatry

    (2011)
  • T.M. Delorey et al.

    Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome

    J. Neurosci.

    (1998)
  • J.T. Den Dunnen et al.

    Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion

    Hum. Mutat.

    (2000)
  • Cited by (96)

    • Posttranslational modifications & lithium's therapeutic effect—Potential biomarkers for clinical responses in psychiatric & neurodegenerative disorders

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Gene mutations (monogenic or polygenic) are likely the main cause and result in alterations to neuronal excitability, synaptic transmission, network development (Pandolfo, 2011), in addition to altered circadian rhythms (Re et al., 2020). Most known mutations affect ion channels, including sodium (Steinlein, 2014), potassium (Maljevic and Lerche, 2014) and calcium (Gambardella and Labate, 2014) voltage-gated channels, as well as the inhibitory ionotropic GABA receptor (Hirose, 2014). The activation, inhibition, trafficking, recycling/internalization, and degradation of these ion channels and receptors are critically regulated by PTMs (Onwuli and Beltran-Alvarez, 2016; Capera et al., 2019; Pei et al., 2018).

    View all citing articles on Scopus
    View full text