AIMS: Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, 
which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, 
mutations in five different genes encoding potassium and calcium channel 
subunits have been reported. We present, for the first time, a novel 
loss-of-function mutation coding for an L-type calcium channel subunit.
METHODS AND RESULTS: The electrocardiogram of the affected member of a single 
family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and 
symmetrical T-waves. Invasive electrophysiological testing showed short 
ventricular refractory periods and increased vulnerability to induce ventricular 
fibrillation. DNA screening of the patient identified no mutation in previously 
known SQTS genes; however, a new variant at a heterozygous state was identified 
in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding 
for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. The pathogenic role 
of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using 
co-expression of the two other L-type calcium channel subunits, Ca(v)1.2α1 and 
Ca(v)β(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these 
cells under voltage-clamp conditions using the whole-cell configuration. 
Co-expression of the p.Ser755Thr Ca(v)α(2)δ-1 subunit strongly reduced the I(Ba) 
by more than 70% when compared with the co-expression of the wild-type (WT) 
variant. Protein expression of the three subunits was verified by performing 
western blots of total lysates and cell membrane fractions of HEK-293 cells. The 
p.Ser755Thr variant of the Ca(v)α(2)δ-1 subunit was expressed at a similar level 
compared with the WT subunit in both fractions. Since the mutant Ca(v)α(2)δ-1 
subunit did not modify the expression of the pore-forming subunit of the L-type 
calcium channel, Ca(v)1.2α1, it suggests that single channel biophysical 
properties of the L-type channel are altered by this variant.
CONCLUSION: In the present study, we report the first pathogenic mutation in the 
CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be 
determined whether mutations in this gene lead to other manifestations of the 
J-wave syndrome.