Fenotipos nanomecánicos en miocardiopatía hipertrófica familiarNanomechanical phenotypes in familial hypertrophic cardiomyopathy

Zusammenfassung

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease. Anatomically, it is mainly characterized by left ventricular hypertrophy, while, at the functional level, HCM hearts suffer from hypercontractility and diastolic impairment. Most HCM-causing variants target genes encoding components of the sarcomere, the basic contractile unit of cardiomyocytes. A main HCM gene is MYBPC3 encoding cardiac myosin-binding proteinC (cMyBP-C), a protein that acts as a negative regulator of contraction by slowing down the sliding of actomyosin filaments during sarcomere shortening. While many HCM-causing MYBPC3 variants result in the premature truncation of the protein, leading to degradation and reduced total cMyBP-C content (i.e. protein haploinsufficiency), a significant proportion of the mare nontruncating. The molecular mechanisms by which nontruncating MYBPC3 variants lead to HCM development are still obscure. To improve our understanding of HCM etiology, this doctoral thesis has examined molecular pathomechanisms by which nontruncating MYBPC3 variants cause disease. To this aim, we first explored whether the induction of proteinhaplo insufficiency drivers defines the pathogenicity of nontruncating MYBPC3 variants. Acurated database of nontruncating MYBPC3 variants with a defined pathogenicity status was built to explore the prevalence of variant-induced RNA splicing alterations and protein destabilization, two major haploinsufficiency drivers. These molecular traits were specifically detected in around 50% of the HCM-linked variants, meaning that the induction of these haploinsufficiency drivers can be used as supporting functional evidence of pathogenicity in the classification of genetic variants found in HCM patients...