Drosophila Models Reveal NAT Complex Roles in Heart Development and Enable Functional Validation of Congenital Heart Disease Variants.

N-terminal acetylation, catalyzed by N-terminal acetyltransferase (NAT) complexes, is one of the most prevalent protein modifications in eukaryotic cells, yet its role in heart development remains poorly understood. Here, we use Drosophila as an in vivo platform to investigate the functions of NAT complex components in cardiac development and congenital heart disease (CHD). Focusing on the NatA complex, we showed that cardiac-specific knockdown of each of its three subunits (Naa15-16, vnc, and san) led to developmental lethality, structural disorganization, fibrosis, and impaired cardiac function in Drosophila. Remarkably, human NAA16 completely rescued the cardiac defects in Naa15-16 silenced Drosophila, whereas a CHD-associated variant (NAA16-R70C) failed to do so, providing direct functional evidence of its pathogenicity. Together, these findings suggest the NatA complex as a critical regulator of heart development and provide functional validation linking variants in NatA complex genes to CHD. Further studies in mammalian models will be required to provide additional supporting evidence.