Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology

Abstract

More than 350 individual MYPBC3 mutations have been identified in patients with inherited hypertrophic cardiomyopathy (HCM), thus representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM. HCM is considered a disease of the sarcomere and is characterized by left ventricular hypertrophy, myocyte disarray and diastolic dysfunction. MYBPC3 encodes for the thick filament associated protein cardiac myosin-binding protein C (cMyBP-C), a signaling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of contraction and relaxation. This review aims to provide a succinct overview of how mutations in MYBPC3 are considered to affect the physiological function of cMyBP-C, thus causing the deleterious consequences observed inHCM patients. Importantly, recent advances to causally treat HCM by repairing MYBPC3 mutations by gene therapy are discussed here, providing a promising alternative to heart transplantation for patients with a fatal form of neonatal cardiomyopathy due to bi-allelic truncating MYBPC3 mutations.

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

“…39 The likelihood of compound heterozygotes or homozygotes in countries with founder mutations is increased. 5 The finding of NCCM and DCM in the FG+ population and within 1 family supports previous suggestions that the various cardiomyopathies are part of a cardiomyopathy spectrum with similar pathogenesis. Lorca et al 40 similarly described the overlapping of HCM and NCCM phenotypes within 1 family.…”

“…5 In this study, a significantly poor outcome was observed in a minority of young NCCM and DCM patients, partly explained by homozygous and compound heterozygous mutations. 39 Because MYBPC3 founder mutations are truncating mutations leading to haploinsufficiency, 8 compound heterozygous or homozygous mutations would theoretically result in human MYBPC3 knockouts (no functional MYBPC3 protein), leading to severe HF at a young age.…”

Correction of a pathogenic gene mutation in human embryos

“…Among these are autosomal dominant mutations, where inheritance of a single copy of a defective gene can result in clinical symptoms. Genes in which dominant mutations manifest as late-onset adult disorders include BRCA1 and BRCA2, which are associated with a high risk of breast and ovarian cancers 1 , and MYBPC3, mutation of which causes hypertrophic cardiomyopathy (HCM) 2 . Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation.…”

“…MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies, including dilated cardiomyopathy and left ventricular non-compaction 6 . MYBPC3 encodes the thick filament-associated cardiac myosin-binding protein C (cMyBP-C), a signalling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of both contraction and relaxation 2 .…”

Do Gene and Cell Therapies will Ultimately Replace Repeated Injections for the Treatment of Chronic Diseases

“…The potential of the gene editing tool CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) phenomenon seems to be the latest experimental use of the technology is creating skin grafts that trigger the release of insulin and help manage diabetes. This comes from the Research that has successfully tested the idea with mice that gained less weight and showed a reversed resistance to insulin because of the grafts [1]. I think this approach could eventually be used to treat a variety of metabolic and genetic conditions, not just diabetes it's a question of using skin cells to trigger different chemical reactions in the body because easy and abundantly available skin cells available at our disposal.…”