De novo CLPTM1 variants with reduced GABAAR current response in patients with epilepsy

Author:

Liu Nana123ORCID,Li Jinliang4,Gao Kai1235,Perszyk Riley E.6,Zhang Jing6,Wang Jingmin1237,Wu Ye123,Jenkins Andrew68,Yuan Hongjie69,Traynelis Stephen F.69,Jiang Yuwu123510ORCID

Affiliation:

1. Department of Pediatrics Peking University First Hospital Beijing China

2. Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases Beijing China

3. Children Epilepsy Center Peking University First Hospital Beijing China

4. Department of Pediatrics Central People's Hospital of Zhanjiang Guangdong China

5. Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission Peking University Beijing China

6. Department of Pharmacology and Chemical Biology Emory University School of Medicine Atlanta Georgia USA

7. Department of Neurology Affiliated Children's Hospital of Capital Institute of Pediatrics Beijing China

8. Department of Pharmaceutical Sciences University of Saint Joseph West Hartford Connecticut USA

9. Center for Functional Evaluation of Rare Variants (CFERV) Emory University School of Medicine Atlanta Georgia USA

10. Center of Epilepsy Beijing Institute for Brain Disorders Beijing China

Abstract

AbstractObjectiveTo investigate the clinical features and potential pathogenesis mechanism of de novo CLPTM1 variants associated with epilepsy.MethodsIdentify de novo genetic variants associated with epilepsy by reanalyzing trio‐based whole‐exome sequencing data. We analyzed the clinical characteristics of patients with these variants and performed functional in vitro studies in cells expressing mutant complementary DNA for these variants using whole‐cell voltage‐clamp current recordings and outside‐out patch‐clamp recordings from transiently transfected human embryonic kidney (HEK) cells.ResultsTwo de novo missense variants related to epilepsy were identified in the CLPTM1 gene. Functional studies indicated that CLPTM1‐p.R454H and CLPTM1‐p.R568Q variants reduced the γ‐aminobutyric acid A receptor (GABAAR) current response amplitude recorded under voltage clamp compared to the wild‐type receptors. These variants also reduced the charge transfer and altered the time course of desensitization and deactivation following rapid removal of GABA. The surface expression of the GABAAR γ2 subunit from the CLPTM1‐p.R568Q group was significantly reduced compared to CLPTM1‐WT.SignificanceThis is the first report of functionally relevant variants within the CLPTM1 gene. Patch‐clamp recordings showed that these de novo CLPTM1 variants reduce GABAAR currents and charge transfer, which should promote excitation and hypersynchronous activity. This study may provide insights into the molecular mechanisms of the CLPTM1 variants underlying the patients’ phenotypes, as well as for exploring potential therapeutic targets for epilepsy.

Funder

Natural Science Foundation of Beijing Municipality

China Scholarship Council

Fundamental Research Funds for the Central Universities

National Institute of Neurological Disorders and Stroke

National Basic Research Program of China

National Natural Science Foundation of China

Publisher

Wiley

Subject

Neurology (clinical),Neurology

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