The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABA A R function.

Autor: Li PP; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Zhou YY; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Gao L; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Lv JN; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Xu SS; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Zhao YW; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Xu D; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Huang R; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Zhang X; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China., Li P; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China., Fu X; Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China., He Z; Department of Pediatric Rehabilitation, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 217191@wzhealth.com.
Jazyk: angličtina
Zdroj: Neuroscience [Neuroscience] 2024 Aug 16; Vol. 553, pp. 172-184. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1016/j.neuroscience.2024.06.029
Abstrakt: Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABA A R) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABA A R. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABA A R channel function, we conducted transient expression experiments using GABA A R subunits in HEK293T cells. The GABA A Rs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABA A R containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABA A R. We propose that GABRB2 variant F224S is pathogenic and GABA A Rs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.
(Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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