Are hypertrophic and dilated cardiomyopathy different mutations in the same gene?

Proteins in cardiac myocytes assemble into contractile units known as sarcomeres. Contractile force is generated by interaction between sarcomeric thick and thin filaments. Whereas sarcomere dysfunction has been identified as the fundamental pathogenic mechanism in hypertrophic cardiomyopathy (HCM), we know relatively little about the molecular basis of idiopathic dilated cardiomyopathy (DCM). However, some cases of familial DCM are caused by mutations in cardiac cytoskeletal proteins. Thus, Kamisago et al found that mutations in sarcomere protein genes account for approximately 10% of cases of familial DCM and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction.

The sarcomeric thin filament protein actin plays a central, dual role in cardiac myocytes, generating contractile force by interacting with myosin and transmitting this force within and between cells. DCM can be caused by mutations in domains of the cardiac actin gene (ACTC) not involved in contractile force generation. More recently, it has been shown that mutation in force-generating domains of ACTC can cause HCM. In other words, defects within functionally distinct ACTC regions can cause fundamentally different cardiomyopathies.

Further reading

Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000;343:1688-1696.

Olson TM, Doan TP, Kishimoto NY, Whitby FG, Ackerman MJ, Fananapazir L Inherited and de novo mutations in the cardiac actin gene

Tropomyosin associates with actin primarily by electrostatic interaction and is thought to act as a mechanical stabilizer of the thin filament. It plays a central regulatory role in excitation-contraction coupling and in muscle by undergoing a conformational change upon calcium binding to the troponin complex. This leads to disinhi-bition of interaction between actin and myosin, resulting in the generation of contractile force.

Olson et al recendy demonstrated that substitution of different amino acid residues in the same thin filament proteins is associated with the distinct phenotypes of cardiac hypertrophy or congestive heart failure. They suggested that the distinct cardiomyopathy phenotypes associated with different tropomyosin mutations result from differential effects on contractile force generation and force transmission. In HCM, regulation of contractile force generation is impaired, activating signaling pathways for myocellular hypertrophy. In DCM, on the other hand, it is the structural integrity of the force-transmitting proteins that is impaired, leading to nonuniform myocyte contraction and increased vulnerability to myocellular injury and death under physiologic mechanical stress. Olson et al have further suggested that the hypertrophy of viable myocytes in DCM caused by defective force-transmitting proteins is outpaced by cumulative cell loss, leading to cardiac dilatation and pump failure cause hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2000;32:1687-1694. Oison TM, Kishimoto NY, Whitby FG, Michels W. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol. 2001 ;33:723-732.


genetics; familial dilated cardiomyopathy; mutations; molecular biology

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