AIMS: Short-QT syndrome (SQTS) is a recently recognized disorder associated with 
atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. 
Mutations in several ion channel genes have been linked to SQTS; however, the 
mechanism remains unclear. This study describes a novel heterozygous 
gain-of-function mutation in the inward rectifier potassium channel gene, KCNJ2, 
identified in SQTS.
METHODS AND RESULTS: We studied an 8-year-old girl with a markedly short-QT 
interval (QT = 172 ms, QTc = 194 ms) who suffered from paroxysmal AF. Mutational 
analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional 
assays displayed no Kir2.1 currents when M301K channels were expressed alone. 
However, co-expression of wild-type (WT) with M301K resulted in larger outward 
currents than the WT at more than -30 mV. These results suggest a 
gain-of-function type modulation due to decreased inward rectification. 
Furthermore, we analysed the functional significance of the amino acid charge at 
M301 (neutral) by changing the residue. As with M301K, in M301R (positive), the 
homozygous channels were non-functional, whereas the heterozygous channels 
demonstrated decreased inward rectification. Meanwhile, the currents recorded in 
M301A (neutral) showed normal inward rectification under both homo- and 
heterozygous conditions. Heterozygous overexpression of WT and M301K in neonatal 
rat ventricular myocytes exhibited markedly shorter action potential durations 
than the WT alone.
CONCLUSION: In this study, we identified a novel KCNJ2 gain-of-function 
mutation, M301K, associated with SQTS. Functional assays revealed no functional 
currents in the homozygous channels, whereas impaired inward rectification 
demonstrated under the heterozygous condition resulted in larger outward 
currents, which is a novel mechanism predisposing SQTS.