Combined, the strong upregulation of plectin and other plakins in models of cholestatic challenge [23,26], the mechanical weakening of the biliary epithelium in the absence of plectin, and the recently reported case of familial intrahepatic cholestasis caused by compound heterozygous mutations in the plectin gene [27], suggest that plectin stabilizes the biliary epithelium, maintains keratin network architecture, and protects the tissue against mechanical stress-induced damage. The gene discussed is PLEC; the disease is familial intrahepatic cholestasis.