Characterization of a novel KCNJ2 sequence variant detected in Andersen-Tawil syndrome patients

BMC Medical Genetics

Research Article

Britt-Maria Beckmann¹  Stefan Kääb¹  Stefanie Scheiper²  Silke Kauferstein²  Brigitte Hertel³  Gerhard Thiel³ 

[1] Department of Medicine I, University Hospital Munich, Ludwig Maximilians University, Munich, Germany;Institute of Legal Medicine, University Hospital Frankfurt, Goethe University, Kennedyallee 104, D-60596, Frankfurt, Germany;Plant Membrane Biophysics, Technical University Darmstadt, Darmstadt, Germany;

关键词: Andersen-Tawil syndrome;    KCNJ2;    Potassium channel Kir2.1;    Functional characterization;   

DOI  :  10.1186/s12881-017-0472-x

 received in 2016-03-03, accepted in 2017-09-27,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundMutations in the KCNJ2 gene encoding the ion channel Kir2.1 have been linked to the Andersen-Tawil syndrome (ATS). Molecular genetic screening performed in a family exhibiting clinical ATS phenotypes unmasked a novel sequence variant (c.434A > G, p.Y145C) in this gene. The aim of this study was to investigate the effect of this variant on Kir2.1 ion channel functionality.MethodsMutant as well as wild type GFP tagged Kir2.1 channels were expressed in HEK293 cells. In order to examine the effect of the new variant, electrophysiological measurements were performed using patch clamp technique. Cellular localization of the mutant in comparison to the wild type ion channel was analyzed by confocal laser scanning microscopy.ResultsThe currents of cells expressing only mutant channels or a mixture of wild type and mutant were significantly reduced compared to those expressing wild type (WT) channels (p < 0.01). Whereas WT expressing cells exhibited at −120 mV an averaged current of −4.5 ± 1.9 nA, the mutant generates only a current of −0.17 ± 0.07 nA. A co-expression of mutant and WT channel generates only a partial rescue of the WT current. Confocal laser scanning microscopy indicated that the novel variant is not interfering with synthesis and/or protein trafficking.ConclusionsThe detected sequence variant causes loss-of-function of the Kir2.1 channel and explains the clinical phenotypes observed in Andersen-Tawil syndrome patients.

【 授权许可】

CC BY   
© The Author(s). 2017