THE CARDIAC MYOSIN HEAVY-CHAIN ARG-403-]GLN MUTATION THAT CAUSES HYPERTROPHIC CARDIOMYOPATHY DOES NOT AFFECT THE ACTIN-BINDING OR ATP-BINDING CAPACITIES OF 2 SIZE-LIMITED RECOMBINANT MYOSIN HEAVY-CHAIN FRAGMENTS

Our aim was to investigate the potential functional consequences of my osin heavy chain (MHC) mutations identified in patients with familial hypertrophic cardiomyopathy. We observed the presence of a mutated bet a-MHC mRNA in a formalin-fixed paraffin-embedded myocardial tissue of a proband from family A, which Geisterfer-Lowrance et al. [Geisterfer- Lowrance, Kass, Tanigawa, Vosberg, McKenna, Seidman and Seidman (1990) Cell 62, 999-1006] identified as carrying the Arg-403 to Gln mutation . Recombinant DNA methods were then used to obtain size-limited, solub le and undenatured fragments of mutated myosin subfragment 1 focused a round the 403 mutation. The present analysis indicated that the 403 mu tation did not quantitatively alter the actin- or ATP-binding capaciti es of two 246-residue or 524-residue-long recombinant MHC fragments co ntaining this mutation. The absence of any apparent impact of the 403 mutation in the recombinant MHC fragments on interactions between acti n and ATP is discussed in relation to numerous biochemical and structu ral reports which demonstrate the crucial role of the central MHC segm ent, where the 403 mutation occurs, in myosin functions.