The discovery in 1990 that a point mutation at residue 403 (R403Q) in the β-myosin heavy chain (MHC) caused a severe form of FHC was the first of many demonstrations linking FHC to mutations in muscle proteins. A mouse model for FHC has been widely used to study the mechanochemical properties of mutated cardiac myosin, but mouse hearts express α-MHC, whereas the ventricles of larger mammals express predominantly β-MHC. To address the role of the isoform backbone on function, we generated a transgenic mouse in which the endogenous α-MHC was partially replaced with transgenically encoded β-MHC or α-MHC. A His6 tag was cloned at the N terminus, along with R403Q, to facilitate isolation of myosin subfragment 1 (S1).
We find in agreement with earlier studies that the R403Q mutation in a mouse α-MHC backbone results in a gain of function, a model that has been widely accepted as the primary cause leading to hypertrophic cardiomyopathy. However, we find that this enhancement does not extend to the R403Q mutation in a mouse β-MHC backbone. Our results do not necessarily imply a universal mechanism for FHC mutations in the β-myosin heavy chain.
NM_000257.4:c.1208G>A (p.Arg403Gln)