Clinical analysis and functional characterization of KCNQ2-related developmental and epileptic encephalopathy

Jia Ye; Siyang Tang; Pu Miao; Zhefeng Gong; Qiang Shu; Jianhua Feng; Yuezhou Li

doi:10.3389/fnmol.2023.1205265

Clinical analysis and functional characterization of KCNQ2-related developmental and epileptic encephalopathy

Front Mol Neurosci. 2023 Jul 11:16:1205265. doi: 10.3389/fnmol.2023.1205265. eCollection 2023.

Authors

Jia Ye^#¹, Siyang Tang^#², Pu Miao^#², Zhefeng Gong³, Qiang Shu², Jianhua Feng³, Yuezhou Li¹

Affiliations

¹ National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Pediatric Department, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.

^# Contributed equally.

Abstract

Background: Developmental and epileptic encephalopathy (DEE) is a condition characterized by severe seizures and a range of developmental impairments. Pathogenic variants in KCNQ2, encoding for potassium channel subunit, cause KCNQ2-related DEE. This study aimed to examine the relationships between genotype and phenotype in KCNQ2-related DEE.

Methods: In total, 12 patients were enrolled in this study for genetic testing, clinical analysis, and developmental evaluation. Pathogenic variants of KCNQ2 were characterized through a whole-cell electrophysiological recording expressed in Chinese hamster ovary (CHO) cells. The expression levels of the KCNQ2 subunit and its localization at the plasma membrane were determined using Western blot analysis.

Results: Seizures were detected in all patients. All DEE patients showed evidence of developmental delay. In total, 11 de novo KCNQ2 variants were identified, including 10 missense variants from DEE patients and one truncating variant from a patient with self-limited neonatal epilepsy (SeLNE). All variants were found to be loss of function through analysis of M-currents using patch-clamp recordings. The functional impact of variants on M-current in heteromericKCNQ2/3 channels may be associated with the severity of developmental disorders in DEE. The variants with dominant-negative effects in heteromeric channels may be responsible for the profound developmental phenotype.

Conclusion: The mechanism underlying KCNQ2-related DEE involves a reduction of the M-current through dominant-negative effects, and the severity of developmental disorders in DEE may be predicted by the impact of variants on the M-current of heteromericKCNQ2/3 channels.

Keywords: KCNQ2; developmental and epileptic encephalopathy; developmental delay; dominant-negative effects; pediatrics.

Grants and funding

This project was supported by the National Natural Science Foundation of China (31871060 and 82101515), the Ministry of Science and Technology of China (2018YFE0112900), and the Key Research and Development Project of Science and Technology Department of Zhejiang Province (2021C03104).