Human KCNE1 ELISA Matched Antibody Pair

Background: The aim of the study was to determine, whether electrocardiogram (ECG) screening could reduce the risk of sudden cardiac death in patients with hearing loss through the early diagnosis of Jervell and Lange-Nielsen syndrome and the introduction of the therapy. Methods: One thousand and eighty patients with hearing loss (aged 21.8 +/- 19.9 years) underwent ECG. Additionally, all subjects were asked to complete a 3-question survey. Those who met, at least, one of the high-risk criteria underwent further cardiac assessment and genetic testing. Results: QTc assessment was possible in 1,027 patients. Mean QTc measured 422.8 +/- 23.7 ms in 313 women, 414.9 +/- 27.7 ms in 273 men and 421.1 +/- 21.5 ms in 441 children (individuals younger than 14 years). Abnormal QTc was found in 13 (4.1%) women, 20 (7.3%) men, and 72 (16.3%) children. In the studied group, no recessive mutation of KNCQ1 or KCNE1 was found. In 6 patients, other mutations were found: in KCNQ1 (n = 1), in KCNH2 (n = 3) and in SCN5A (n = 1), which were pathogenic for long-QT-syndromes (LQTS), and 2 mutations of unknown clinical significance in SCN5A. Overall, out of these 6 patients LQTS was diagnosed in 3 asymptomatic patients, but with abnormal QTc and in 2 patients with normal QTc, but who were previously treated for epilepsy. Conclusions: Jervell and Lange-Nielsen syndrome is a very rare condition even in a population with hearing loss. In this population, the prevalence of prolonged QT interval is increased over the general population. Further investigations are necessary.

KCNQ1 (Kv7.1 or KvLQT1) plays important physiological roles in various tissues forming potassium channels with KCNE subunits. Among the channels formed by KCNQ1 and KCNE subunits, the best studied is the slow delayed rectifier potassium channel in the heart, the I-Ks (KCNQ1/KCNE1) channel, which is critical for repolarization of cardiac action potential. The KCNQ1 channel is internalized by Nedd4/Nedd4-like ligase-dependent ubiquitination. It is also reported that phosphorylation of KCNE1 by PKC results in internalization of the KCNQ1/KCNE1 channel. Because we have observed down-regulation of KCNQ1/KCNE1 currents by activation of the alpha(1)-adrenergic receptor (alpha(1)AR) that activates PKC, this study investigated whether alpha(1)AR causes internalization of the KCNQ1 protein. We fused HaloTag to the extracellular region of KCNQ1 (Halo-KCNQ1) and co-expressed it with alpha(1)ARs in HEK293 cells. The KCNQ1 protein on the cell surface was selectively labeled with membrane-impermeable HaloTag ligands, and changes in its localization were monitored by confocal fluorescence microscopy. Activation of alpha(1A)AR and alpha(1B)AR caused marked internalization of KCNQ1, which was not KCNE1-dependent. Internalization of KCNQ1 by alpha(1)AR activation was inhibited by disruption of the PY motif or the YXXF motif in the C-terminus. Double staining for the receptor and the channel revealed that KCNQ1 internalization was independent of alpha(1)AR internalization. Our results suggest that alpha(1)AR-mediated direct internalization of KCNQ1 is AP2/clathrin-dependent and may be triggered by ubiquitination of KCNQ1 via the AMP dependent kinase (AMPK)/Nedd4-2 pathway. When phenylephrine was applied to rat neonatal cardiomyocytes transfected with KCNQ1 and alpha(1)AR, the KCNQ1 protein was internalized. The internalization of KCNQ1 by alpha(1)AR would affect pathophysiology in a variety of tissues expressing KCNQ1, which merits further in vivo study.