Genotypic effect of a mutation of the MYBPC3 gene and two phenotypes with different patterns of inheritance

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology

Background:

• MYBPC3 gene mutations are associated with both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).
• The specific MYBPC3 mutation c.3373G>A was previously identified as a cause of autosomal recessive HCM.
• This study investigates a novel presentation of this mutation.

Purpose of the Study:

• To identify the genetic cause of DCM in a family with suspected inherited heart disease.
• To characterize the inheritance pattern and molecular mechanism of a MYBPC3 mutation.
• To explore the role of MYBPC3 in Iranian DCM and HCM patients.

Main Methods:

• Next-generation sequencing of 23 candidate genes followed by Sanger sequencing.
• Computational analyses including protein modeling and in silico functional predictions (I-TASSER, Phyre2).
• Analysis of MYBPC3 protein structure and function.

Main Results:

• A MYBPC3 variant, c.3373G>A (p.Val1125Met), was identified, exhibiting autosomal dominant inheritance in the studied family.
• Computational predictions indicated a high pathogenicity score for the mutation.
• In silico analysis revealed significant alterations in the secondary structure of the mutated cMyBP-C protein.

Conclusions:

• The MYBPC3 mutation c.3373G>A can cause autosomal dominant DCM, distinct from its previously known role in autosomal recessive HCM.
• The zygosity of the MYBPC3 mutation may influence its effect on cellular mechanisms in cardiomyopathies.
• MYBPC3 is implicated as a significant gene in the etiology of DCM and HCM in the Iranian population.