Genetic mutations and mechanisms in dilated cardiomyopathy

Abstract

Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are "private" or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.

Figure 1. Morphological changes to the heart in cardiomyopathy.

(A) Normal heart. (B) In DCM, the heart enlarges with increased diameter and reduced function. (C) In HCM, the myocardium — especially in the LV — becomes thickened, leading to impaired filling and emptying.

Figure 2. The sarcomere is a target for cardiomyopathy mutations.

(A) The sarcomere from Z disc to Z disc. Electron micrograph of a sarcomere from a human heart. The TTN gene encoding the giant protein titin is mutated in DCM. Titin’s amino terminus anchors in the Z band, and its carboxy terminus ends in the M band. The titin kinase (TK) domain is found at the carboxy terminus and, when mutated, results in impaired stretch sensing and signaling. Titin interacts with both the thin and thick filaments. The thick-filament proteins (grey) are encoded by MYH7 and MYBPC3, two genes commonly linked to HCM. (B) Isoforms of titin. Alternative splicing in the region of titin that encodes the I band gives rise to isoforms with varying spring properties. The N2B isoform is found exclusively in cardiac muscle and the N2A isoform in skeletal muscle. The N2BA isoform is also found in cardiac muscle and contains features found in both N2B and N2A titin. N2BA titin has a longer extensible I band region than N2B titin, making it more compliant. US, unique sequence; Fn, fibronectin domains; PEVK, repeating units of amino acids (proline, glutamic acid, valine, and lysine).

Figure 3. A view of the cardiomyocyte.

The cytoplasm of the cardiomyocyte contains sarcomeres, which contain thin and thick filaments. Mutations in sarcomere genes lead to HCM and DCM. Plasma membrane–associated proteins such as dystrophin and its associated proteins, the sarcoglycans, are mutated in inherited DCM associated with skeletal muscle disease. Mutations of genes encoding nuclear membrane proteins such as lamins A and C, emerin, and nesprins lead to inherited DCM due to an inappropriate transcriptional response to mechanical stress. Many of these nuclear membrane genes also induce cardiac conduction system disease.

Figure 4. Fibrosis occurs commonly in DCM.

Cardiac MRI of a patient with an MYH7 mutation. (A) Short-axis view sectioning through the LV shows late gadolinium enhancement, which indicates fibrosis. Late gadolinium enhancement is visualized as white regions (arrows) and is never seen in a normal heart. (B) Four-chamber view shows late gadolinium enhancement (arrows) in the same MYH7 mutant individual.