OBJECTIVE: The Andersen's syndrome is a hereditary disease, which is 
characterized by cardiac arrhythmias, periodic paralysis and dysmorphic 
features. Recently, mutations of the KCNJ2 gene, which encodes the inward 
rectifying potassium channel subunit Kir2.1, have been identified in affected 
individuals. However, the functional effects of these mutations have not yet 
been fully elucidated.
METHODS AND RESULTS: To clarify this situation we generated known Andersen 
disease mutants of KCNJ2 which did not yield any measurable K(+) currents in CHO 
cells indicating that the Andersen mutants failed to form functional 
homomultimeric complexes. EGFP-tagged KCNJ2 wild-type and mutant channels 
distributed in a similar homogeneous pattern in the cell membrane suggesting 
that protein trafficking was not altered by the Andersen mutations but rather 
implicating that the mutations rendered the KCNJ2 channel non-functional. In 
heterologous coexpression experiments the Andersen mutants exerted a 
dominant-negative effect on wild-type KCNJ2. However, the extent of suppression 
varied between the different KCNJ2 mutants. Given our results in CHO cells, we 
expressed the disease mutant KCNJ2-S136F in neonate rat cardiomyocytes using 
adenoviral gene transfer to test the effect of Andersen mutants on native I(K1). 
I(K1) density was indeed significantly reduced in KCNJ2-S136F-infected cells 
(n=9) compared to control cells (n=9) over a voltage range from -70 to -150 mV 
(P<0.05).
CONCLUSION: These results support that Kir2.x channels are a critical component 
of native I(K1) in neonate rat cardiomyocytes and that a dominant-negative 
suppression of I(K1) in native cells is the pathophysiological correlate of the 
Andersen's syndrome.