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Vogel, F.D.* ; Krenn, M.* ; Westphal, D.S.* ; Graf, E.* ; Wagner, M. ; Leiz, S.* ; Koniuszewski, F.* ; Augé-Stock, M.* ; Kramer, G.* ; Scholze, P.* ; Ernst, M.*

A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.

Epilepsia 63, e35-e41 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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Variants in γ-aminobutyric acid A (GABAA) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4-subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early-onset drug-resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore-forming domain, shows accelerated desensitization and a lack of seizure-protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Drug-resistant Epilepsy ; Early-onset Epilepsy ; Gaba Receptors A ; Neurosteroid ; Tonic Inhibition ; Trio Exome Sequencing; Gaba(a) Receptors; Epilepsies; Genes
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 0013-9580
e-ISSN 1528-1167
Journal Epilepsia
Quellenangaben Volume: 63, Issue: 4, Pages: e35-e41 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
Grants Austrian Science Fund
DOI 10.1111/epi.17188
WOS ID WOS:000754329500001
Scopus ID 85124546195
PubMed ID 35152403
Erfassungsdatum 2022-06-24
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