Through analysis of mice in which CS mutations were introduced to the equivalent loci in the mouse KCNJ8 and ABCC9 genes, we previously demonstrated that vascular smooth muscle hypoexcitability underlies the cardiovascular features of CS (3, 22), but the multifaceted presentation in other tissues is not easily explained by chronic vascular dilation. The gene discussed is KCNJ8; the disease is Cowden syndrome 1.