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MYH6
Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.
MHC-α is a 224 kDa protein composed of 1939 amino acids. The MYH6 gene is located on chromosome 14q12, approximately ~4kb downstream of the MYH7 gene encoding the other major cardiac muscle isoform of myosin heavy chain, MHC-β. MHC-α is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle; it is the predominant isoform expressed in human cardiac atria, and the lesser expressed isoform (7%) expressed in human cardiac ventricles. MHC-α is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-α head non-covalently binds two light chains, atrial essential light chain (MYL4) and atrial regulatory light chain (MYL7). Approximately 300 myosin molecules constitute one thick filament.
MHC-α isoform is abundantly expressed in both cardiac atria and cardiac ventricles during embryonic development. Following birth, cardiac ventricles predominantly express the MHC-β isoform and cardiac atria predominantly express the MHC-α isoform.
The two isoforms of cardiac MHC, α and β, display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β.
It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards, then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.
The first mutation identified in MYH6 by Niimura et al. was found in a patient population with late-onset hypertrophic cardiomyopathy. An Arg to Gln variant was found at position 795 (Arg795Gln). This mutation was located in a region of MHC-α shown to be important for binding essential light chain. Subsequent studies have also found additional mutations in MYH6 linked to both hypertrophic cardiomyopathy and dilated cardiomyopathy.
Mutations in MYH6 cause atrial septal defect. One underlying mutation is a missense substitution at Ile820Asn, which alters the association of alpha-myosin heavy chain with regulatory light chain. MYH6 has been shown to be the predominant sarcomeric disease gene for secundum-type atrial septal defects. Additional studies unveiled an association between MYH6 mutations and a wide array of cardiac malformations in addition to atrial septal defect, including one non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations.
MYH6 has also been identified as a susceptibility gene for sick sinus syndrome. A missense mutation at Arg721Trp was identified as conferring a lifetime risk of 50% for carriers. An in-frame 3-bp deletion mutation in MYH6, in which one residue in MHC-α is removed, enhances the binding of MHC-α to myosin binding protein-C and disrupts normal sarcomere function and cardiac atrial conduction velocity.
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MYH6
Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.
MHC-α is a 224 kDa protein composed of 1939 amino acids. The MYH6 gene is located on chromosome 14q12, approximately ~4kb downstream of the MYH7 gene encoding the other major cardiac muscle isoform of myosin heavy chain, MHC-β. MHC-α is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle; it is the predominant isoform expressed in human cardiac atria, and the lesser expressed isoform (7%) expressed in human cardiac ventricles. MHC-α is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-α head non-covalently binds two light chains, atrial essential light chain (MYL4) and atrial regulatory light chain (MYL7). Approximately 300 myosin molecules constitute one thick filament.
MHC-α isoform is abundantly expressed in both cardiac atria and cardiac ventricles during embryonic development. Following birth, cardiac ventricles predominantly express the MHC-β isoform and cardiac atria predominantly express the MHC-α isoform.
The two isoforms of cardiac MHC, α and β, display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β.
It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards, then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.
The first mutation identified in MYH6 by Niimura et al. was found in a patient population with late-onset hypertrophic cardiomyopathy. An Arg to Gln variant was found at position 795 (Arg795Gln). This mutation was located in a region of MHC-α shown to be important for binding essential light chain. Subsequent studies have also found additional mutations in MYH6 linked to both hypertrophic cardiomyopathy and dilated cardiomyopathy.
Mutations in MYH6 cause atrial septal defect. One underlying mutation is a missense substitution at Ile820Asn, which alters the association of alpha-myosin heavy chain with regulatory light chain. MYH6 has been shown to be the predominant sarcomeric disease gene for secundum-type atrial septal defects. Additional studies unveiled an association between MYH6 mutations and a wide array of cardiac malformations in addition to atrial septal defect, including one non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations.
MYH6 has also been identified as a susceptibility gene for sick sinus syndrome. A missense mutation at Arg721Trp was identified as conferring a lifetime risk of 50% for carriers. An in-frame 3-bp deletion mutation in MYH6, in which one residue in MHC-α is removed, enhances the binding of MHC-α to myosin binding protein-C and disrupts normal sarcomere function and cardiac atrial conduction velocity.
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