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

Vogel, Florian D.; Krenn, Martin; Westphal, Dominik S.; Graf, Elisabeth; Wagner, Matias; Leiz, Steffen; Koniuszewski, Filip; Auge-Stock, Maximilian; Kramer, Georg; Scholze, Petra und Ernst, Margot (2022): A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype. In: Epilepsia, Bd. 63, Nr. 4, E35-E41

Abstract

Variants in gamma-aminobutyric acid A (GABA(A)) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the alpha 4-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0013-9580
• Sprache: Englisch