Patient-specific hiPSC-derived cardiomyocytes indicate allelic and contractile imbalance as pathogenic factor in early-stage Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is often caused by heterozygous mutations in β-myosin heavy chain (MYH7, β-MyHC). In addition to hyper- or hypocontractile effects of HCM-mutations, heterogeneity in contractile function (contractile imbalance) among individual cardiomyocytes was observed in end-stage HCM-myocardium. Contractile imbalance might be induced by burst-like transcription, leading to unequal fractions of mutant versus wildtype mRNA and protein in individual cardiomyocytes (allelic imbalance).

AQUA Mutant Protein Quantification of Endomyocardial Biopsy-Sized Samples From a Patient With Hypertrophic Cardiomyopathy.

In genetic diseases like hypertrophic cardiomyopathy, reliable quantification of the expression level of mutant protein can play an important role in disease research, diagnosis, treatment and prognosis. For heterozygous β-myosin heavy chain (β-MyHC) mutations it has been shown that disease severity is related to the fraction of mutant protein in the myocardium. Yet, heart tissue from patients with genetically characterized diseases is scarce.

Generation of two iPSC clones (MHHi021-A and MHHi021-B) from a patient with hypertrophic cardiomyopathy with p.Arg723Gly mutation in the MYH7 gene.

Hypertrophic cardiomyopathy (HCM) is the most common form of genetic heart disease and is characterized by abnormal thickening of the left ventricular wall and interventricular septum. Here we describe the generation of two induced pluripotent stem cell (iPSC) clones from a HCM patient, heterozygous for the p.Arg723Gly (c.

Burst-Like Transcription of Mutant and Wildtype -Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) has been related to many different mutations in more than 20 different, mostly sarcomeric proteins. While development of the HCM-phenotype is thought to be triggered by the different mutations, a common mechanism remains elusive. Studying missense-mutations in the ventricular beta-myosin heavy chain (β-MyHC, ) we hypothesized that significant contractile heterogeneity exists among individual cardiomyocytes of HCM-patients that results from cell-to-cell variation in relative expression of mutated vs.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1.