Abnormal Cellular Phenotypes Induced by Three TMPO/LAP2 Variants Identified in Men with Cardiomyopathies

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• A missense variant in the TMPO/LAP2α gene was previously linked to cardiomyopathy.
• The role of TMPO/LAP2α in cardiac muscle requires further investigation.

Purpose of the Study:

• To evaluate the role of TMPO variants in cardiomyopathy.
• To identify novel TMPO variants associated with hypertrophic or dilated cardiomyopathy.

Main Methods:

• Screening of approximately 5000 patients for TMPO variants.
• Utilizing cellular models to analyze the functional impact of identified variants.
• Comparing LAP2α expression in male and female mouse hearts.

Main Results:

• Three novel rare TMPO heterozygous variants were found in six males with cardiomyopathy.
• Identified frameshift and missense variants affecting LAP2α protein function, including haploinsufficiency, altered protein localization, and disrupted interactions with HMGN5, BAF, and E2F1.
• Lower LAP2α expression was observed in male mouse left ventricles compared to females.

Conclusions:

• TMPO/LAP2α variants lead to altered cell proliferation, chromatin structure, and gene expression.
• These findings suggest a potential sex-dependent role for LAP2α in myocardial function and disease development.