Rare variants in the GABAA receptor subunit ε identified in patients with a wide spectrum of epileptic phenotypes.

Fenja Markus, Chloé Angelini, Aurelien Trimouille, Gabrielle Rudolf, Gaetan Lesca, Cyril Goizet, Eulalie Lasseaux, Benoit Arveiler, Marjon Slegtenhorst, Alice S. Brooks, Rami Abou Jamra, Georg‐Christoph Korenke, John Neidhardt, Marta Owczarek‐Lipska
Mol Genet Genomic Med. 2020-06-25; 8(9):
DOI: 10.1002/mgg3.1388

PubMed
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1. Mol Genet Genomic Med. 2020 Sep;8(9):e1388. doi: 10.1002/mgg3.1388. Epub 2020 Jun
25.

Rare variants in the GABAA receptor subunit ε identified in patients with a wide
spectrum of epileptic phenotypes.

Markus F(1)(2), Angelini C(3), Trimouille A(3), Rudolf G(4)(5), Lesca G(6),
Goizet C(3)(4), Lasseaux E(3), Arveiler B(3), van Slegtenhorst M(7), Brooks
AS(7), Abou Jamra R(8), Korenke GC(9), Neidhardt J(2)(10), Owczarek-Lipska
M(1)(2).

Author information:
(1)Junior Research Group, Genetics of Childhood Brain Malformations, Faculty
VI-School of Medicine and Health Sciences, University of Oldenburg, Oldenburg,
Germany.
(2)Human Genetics, Faculty VI-School of Medicine and Health Sciences, University
of Oldenburg, Oldenburg, Germany.
(3)Service de Génétique médicale, CHU de Bordeaux, Bordeaux, France.
(4)CNRS U7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et
Cellulaire, Illkirch, France.
(5)Service de Neurologie, Centre de Références des Maladies Neurogénétique Rares,
Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
(6)Genetics department, Lyon University Hospital and University of Lyon, Lyon,
France.
(7)Department of Clinical Genetics, Erasmus MC University Medical Center,
Rotterdam, The Netherlands.
(8)Institute of Human Genetics, University Medical Center Leipzig, Leipzig,
Germany.
(9)Department of Neuropediatrics, University Children’s Hospital, Oldenburg,
Germany.
(10)Research Center Neurosensory Science, University of Oldenburg, Oldenburg,
Germany.

BACKGROUND: Epilepsy belongs to a group of chronic and highly heterogeneous brain
disorders. Many types of epilepsy and epileptic syndromes are caused by genetic
factors. The neural amino acid y-aminobutyric acid (GABA) is a major inhibitory
neurotransmitter in the mammalian central nervous system. It regulates activity
of channel pores by binding to transmembrane GABA-receptors (GABRs). The GABRs
are heteropentamers assembled from different receptor subunits (α1-6, β1-3, γ1-3,
δ, ε, θ, π, and ρ1-3). Several epileptic disorders are caused by mutations in
genes encoding single GABRs.
METHODS: We applied trio- and single-whole exome sequencing to search for genetic
sequence variants associated with a wide range of epileptic phenotypes
accompanied by intellectual disability and/or global developmental delay in the
investigated patients.
RESULTS: We identified four hemizygous sequence variants in the GABAA receptor
subunit ε gene (GABRE), including one nonsense (NM_004961.3: c.399C>A,
p.Tyr133*), two missense variants (NM_004961.3: c.664G>A, p.Glu222Lys;
NM_004961.3: c.1045G>A, p.Val349Ile), and one variant affecting the translation
initiation codon (NM_004961.3: c.1A>G, p.Met1?) in four unrelated families.
CONCLUSION: Our clinical and molecular genetic findings suggest that GABRE is a
likely candidate gene for epilepsy. Nevertheless, functional studies are
necessary to better understand pathogenicity of the GABRE-mutations and their
associations with epileptic phenotypes.

© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley
Periodicals LLC.

DOI: 10.1002/mgg3.1388
PMCID: PMC7507344
PMID: 32588540 [Indexed for MEDLINE]

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