Dysregulation of N-terminal acetylation causes cardiac arrhythmia and cardiomyopathy.

Summary

This mechanistic study identifies a previously unreported NAA10 p.(Arg4Ser) variant that segregates with QT prolongation, cardiomyopathy, and developmental delay in a large kindred, implicating dysregulated N-terminal acetylation as a disease mechanism. The findings link protein acetylation biology to human cardiac electrophysiology and structure, highlighting a new pathogenic pathway.

Key Findings

• A previously unidentified NAA10 p.(Arg4Ser) variant segregated with QT prolongation, cardiomyopathy, and developmental delay in a large kindred.
• Dysregulation of N-terminal acetylation was implicated as a causal mechanism for cardiac arrhythmia and cardiomyopathy.
• The study links protein N-terminal acetylation biology to human cardiac electrical and structural disease.

Clinical Implications

While early-stage, these findings support considering NAA10 and N-terminal acetylation pathways in genetic evaluation of arrhythmia/cardiomyopathy and motivate development of modulators of protein acetylation as future therapeutics.

Limitations

• Limited sample centered on a single kindred; broader generalizability requires additional cohorts
• Translational therapeutic implications remain to be tested in preclinical models

Future Directions

Validate NAA10-related acetylation defects across independent cohorts; delineate downstream substrates/pathways; assess therapeutic modulation of N-terminal acetylation in preclinical models.