Recessive TMOD1 mutation causes childhood cardiomyopathy.

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Familial cardiomyopathy in children is often linked to genetic mutations but poorly understood.
• Pathogenic variants in specific genes can lead to early-onset heart conditions.

Purpose of the Study:

• To identify the genetic cause of childhood-onset dilated and restrictive cardiomyopathy in two families.
• To elucidate the molecular mechanism by which a TMOD1 variant leads to cardiomyopathy.

Main Methods:

• Whole exome sequencing to identify genetic variants.
• Protein analysis, biochemistry, and studies in cultured cardiomyocytes.
• Structural modeling and assessment of actin filament regulation.

Main Results:

• A homozygous TMOD1 variant (c.565C>T, p.R189W) was identified in affected individuals.
• The TMOD1 R189W variant showed altered protein folding and reduced affinity for actin.
• Mutant TMOD1 impaired actin filament length regulation in cardiomyocytes.

Conclusions:

• The TMOD1 p.R189W variant is a novel cause of childhood-onset cardiomyopathy.
• This variant disrupts cardiac muscle function through impaired actin dynamics.
• The study reveals a new mechanism underlying pediatric heart disease.