PLN Mutations Related to Human Cardiomyopathy

Cardiomyopathy is defined as a disease of the myocardium associated with structural and/or functional disorder. Gene mutations, including the PLN gene, have been intensively identified in cardiomyopathy (Haghighi et al., 2014; Fatkin et al.,

• 2014) . Most of the mutations in the PLN gene cause dilated cardiomyopathy, a distinct form of myocardium disorder characterized by heart chamber dilation with severe contractile dysfunction and a frequent association with heart failure. Among PLN mutations, R9C and R14del mutations in the PLN gene have the highest incidence and are associated with an increase in the inhibitory effect on the Ca²+ affinity of SERCA2 (Schmitt et al., 2003; van Rijsingen et al., 2014; Fish et al., 2016; Ablorh and Thomas,
• 2015) . These findings were also observed in mouse models harboring the R9C or R14del-PLN mutation (Schmitt et al., 2003; Haghighi et al., 2012). Heterozygous R14del carriers develop left ventricular dilation, episodic ventricular arrhythmias, and death by middle age (Haghighi et al., 2006). R14del-PLN transgenic mice exhibited super-inhibition of SERCA2a, which resulted in early death (Haghighi et al., 2006). Interestingly, this PLN mutation also causes arrhythmiogenic right ventricular cardiomyopathy in humans (van Rijsingen et al., 2014). The third human PLN mutation (Leu 39 stop) was also identified to cause dilated cardiomyopathy and premature death in the homozygous state, although heterozygous carriers showed asymptomatic cardiac hypertrophy without alterations in cardiac function (Haghighi et al., 2003). In addition, a recent study has identified a novel R25C mutation that is associated with super-inhibition of Ca²+ cycling and ventricular arrhythmia (Liu et al., 2015). Moreover, mutations in the promoter region of the PLN gene have also been identified in patients with cardiomyopathy by several researchers, including us (Minamisawa et al., 2003; Haghighi et al., 2008; Medin et al., 2007).

It should be noted that SERCA2 mutations have been found in patients with Darier disease, which is characterized by keratotic papules of seborrheic areas of the skin (keratosis follicularis) (Dhitavat et al., 2004; Savignac et al., 2011), but not reported in patients with cardiomyopathy. Intriguingly, patients with Darier disease do not usually display any cardiac dysfunction (Tavadia et al., 2001). So far there is no clear explanation why SERCA2 mutations do not cause cardiomyopathy even though several mutations in Darier disease have been found in the PLN- interacting region.