MYBPC3 mutations in Cardiomyopathy induced different pathway associated with different phenotypes

Abstract

MYBPC3 mutation is the common cause of inherited cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy (LVNC). Herein, we described two patients, who presented with different phenotype of LVNC and HCM, and just harboured similar compounded heterozygous MYBPC3 mutations. We try to compare the clinical information of patients, including pathological features, whole-exomes sequence data, and myocardium gene-expression profiles, to reveal the causing of different phenotypes. Left ventricular myocardium of patients presented with remarkable myocardial interstitial fibrosis and hypertrophic cardiomyocytes. Patient LVNC harboured bi-allelic MYBPC3 (p.R943X and p.R502Q) and patient HCM harbored MYBPC3 (p.W916X and p.G507R). Nonsense mutation induced decreased expression of cMyBP-C significantly but no truncated production were reveal. However, genes related with cardiac myofibroblasts activation, cardiac inflammation and cardiac-collagen accumulation were dramatically upregulated in the LVNC sample, whereas the anti-fibrotic factor was corresponded downregulated in HCM sample, suggested different remodeling pathways were triggered. Exome sequence analysis suggested the cumulative effect of mutant polygene contributed to phenotype of cardiomyopathy. These results indicate that compound MYBPC3 mutations induce cardiomyocyte hypertrophy and secondary to cardiac interstitial fibrosis. The phenotype and symptom of primary cardiomyopathy were caused by interaction effect of multiple mutant genes. Compound MYBPC3 mutations induced to haploinsufficiency and dysfunction of cMyBP-C, and triggered different disease pathway and associated with different phenotypes.