Myosin Binding Protein C Mutations and Hypertrophic Cardiomyopathy: Haploinsufficiency, Deranged Phosphorylation and Cardiomyocyte Dysfunction

Abstract

the four important S4 arginine residues on the voltage-sensing paddle is still unknown, with some models placing them in an aqueous crevice, and others a lipid environment. To learn more about the intricate role of lipid in the structure and function of potassium channels we have studied deuterium and phosphate ESEEM on spin-labeled, liposome reconstituted KcsA. By scanning the trans-membrane helices of KcsA, we show that deuterium coupling can be used to determine residue depth within a lipid bilayer. In addition, residues that interact with the phosphate head-groups of the lipid can be determined by phosphate coupling, and their precise location modeled.

Mortality Risk of Untreated Myosin-Binding Protein C–Related Hypertrophic Cardiomyopathy

“…Most of these mutations are nonsense or frameshift mutations that are supposed to result in truncated proteins, suggesting haploinsufficiency (9,12,13). Almost 25% of the Dutch patients with HCM carry the c.2373dup (originally described as c.2373_2374insG, p.Trp792ValfsX41) founder mutation in MYBPC3 (14).…”

“…As shown in Figure 4, we observed no differences in survival between the subjects with a c.2373dup mutation and the other truncating mutations. It is likely that these mutations share a common pathophysiological mechanism (13), and that FTMR data on one of them are potentially relevant to the vast majority of the MYBPC3 patients and as such for approximately 30% of all patients with HCM.…”

Mechanical and Energetic Consequences of HCM-Causing Mutations

“…Most mutations appear to act as dominant negatives and the mutant proteins are incorporated into the sarcomere where they can affect contractile performance (e.g., [12,10]). A significant exception to this is likely to be the numerous truncation mutations in cMyBP-C for which evidence of haplo-insufficiency has been recently generated [68,69].…”

“…These changes are accompanied by reduction (25-35%) in myofibril cMyBP-C content, a direct consequence of the truncation mutations. Though the increased Ca 2+ -sensitivity may be a secondary consequence of altered phosphorylation levels of the sarcomeric proteins [68], previous functional studies, in which cMyBP-C has been partially extracted from skinned animal cardiomyocytes, indicate that the observed reduction in protein content in human HCM myocytes may be sufficient to cause both the observed mechanical changes [22,30].…”

“…Recent force measurements in mechanically disrupted Triton-permeabilized cardiomyocytes from HCM patients carrying truncation mutations in cMyBP-C show, compared with controls, a decrease in maximal isometric force per cross-sectional area and an increase in myofilament Ca 2+ -sensitivity [68,25]. These changes are accompanied by reduction (25-35%) in myofibril cMyBP-C content, a direct consequence of the truncation mutations.…”