A rare human sequence variant reveals myocardin autoinhibition

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Genetics

Background:

• Myocardin (MYOCD) is a key transcriptional co-activator for cardiac and smooth muscle gene programs.
• Interactions with MEF2 and SRF mediate MYOCD's function.
• Truncated MYOCD isoforms exhibit higher activity, but the mechanism is unclear.

Purpose of the Study:

• Investigate the mechanism behind differential MYOCD isoform activity.
• Characterize a novel MYOCD mutation (K259R) found in a congenital heart disease patient.
• Elucidate the role of MYOCD's amino terminus in cardiac versus smooth muscle gene regulation.

Main Methods:

• Human sequence variation analysis in MYOCD.
• Assessment of MYOCD isoform activity and SRF binding.
• Functional studies on fibroblast conversion and cardiomyocyte hypertrophy.

Main Results:

• A missense mutation (K259R) created a hypomorphic cardiac MYOCD isoform with impaired SRF binding.
• The cardiac-specific amino terminus acts autoinhibitory, repressing SRF-dependent MYOCD activity.
• This repression is enhanced in the K259R mutant and affects smooth muscle cell differentiation and cardiomyocyte growth.

Conclusions:

• A novel autoinhibitory mechanism of the MYOCD amino terminus in cardiac gene regulation was identified.
• This mechanism is differentially regulated between cardiac and smooth muscle.
• Findings provide insights into MYOCD function in congenital heart disease and muscle development.