Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss

Molecular Brain

Micro Report

Gerald W. Zamponi¹  Norbert Weiss²  Robin N. Stringer³  Leos Cmarko⁴  Michel De Waard⁵ 

[1] Department of Clinical Neurosciences, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada;Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic;Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic;Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic;Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic;Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic;Nantes Université, CNRS, INSERM, l’Institut du Thorax, Nantes, France;Nantes Université, CNRS, INSERM, l’Institut du Thorax, Nantes, France;

关键词: Ion channels;    Calcium channels;    T-type channels;    CACNA1H;    Ca3.2;    Mutation;    Epilepsy;    Hearing;    Channelopathy;   

DOI  :  10.1186/s13041-023-01058-2

 received in 2023-08-14, accepted in 2023-09-14,  发布年份 2023

来源: Springer

【 摘 要 】

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss—apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.

【 授权许可】

CC BY   
© Min Zhuo, Bong-Kiun Kaang and BioMed central Ltd. 2023

【 图 表 】

Fig. 2