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

Autor:	Florian D. Vogel, Martin Krenn, Dominik S. Westphal, Elisabeth Graf, Matias Wagner, Steffen Leiz, Filip Koniuszewski, Maximilian Augé‐Stock, Georg Kramer, Petra Scholze, Margot Ernst
Rok vydání:	2022
Předmět:	Epilepsy Phenotype Neurology Neurodevelopmental Disorders Seizures Mutation Missense Humans Drug-resistant Epilepsy Early-onset Epilepsy Gaba Receptors A Neurosteroid Tonic Inhibition Trio Exome Sequencing Neurology (clinical) Receptors GABA-A
Zdroj:	Epilepsia 63, e35-e41 (2022)
ISSN:	1528-1167 0013-9580
DOI:	10.1111/epi.17188
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9b8dd1c16c323db20cc17eaf35ecfb3 https://doi.org/10.1111/epi.17188 Zobrazit plný text záznamu Plný text