Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a severe heart muscle disease leading to sudden cardiac death. The S358L mutation of TMEM43 was first identified in 15 Newfoundland families of ARVC. This mutation is associated with ARVC5, a severe subtype of ARVC with full penetrance and a high percentage of death in patients. Although some studies have revealed that the TMEM43 mutant alters the localization of cardiac proteins, the interaction protein networks of TMEM43 and how the S358L mutation influences the interaction in ARVC remain to be explored. Thus We analyzed the binding partners of TMEM43 and determined the differential interaction proteins of TMEM43 upon S358L mutation.