The multifaceted phenotype of the knockout mouse for the KCNE1 potassium channel gene.

Mutations of the KCNE1 gene (IsK, minK) are related to hereditary forms of cardiac arrhythmias, so-called long QT syndromes (LQT). Here we review the phenotype of a mouse model for the recessive form of LQT known as Jervell and Lange-Nielsen syndrome. KCNE1 knockout mice exhibit an enhanced QT-RR adaptability, which is probably part of the pathophysiological mechanism leading to life-threatening tachyarrhythmia in patients. Like patients, knockout mice are deaf and show vestibular symptoms due to an impaired endolymph production. Knockout mice show urinary and fecal salt wasting and volume depletion. The renal phenotype is due to diminished reabsorption of Na(+) and glucose. The mice are hypokalemic and have increased aldosterone levels. Besides volume depletion, aldosterone is elevated via a set-point shift for sensing of extracellular K(+) in aldosterone-secreting glomerulosa cells, which physiologically express KCNE1. In conclusion, KCNE1 knockout leads to a complex phenotype resulting from direct loss of KCNE1 and compensatory mechanisms. Murine KCNE1 physiology could be helpful for the pathophysiological understanding and perhaps gene-specific treatment of long QT patients.