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.

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

“…Next-generation sequencing has revealed considerable genotypic heterogeneity among the common cardiomyopathic phenotypes (hypertrophic, dilated, restrictive and arrhythmogenic RV dysplasia), although mutations in cytoskeletal, Z-disk, mitochondrial and calcium handling proteins are prominently featured in the dilated phenotype 1,2 . The profound loss of cardiac function present in advanced DCM points to disruption in the molecular pathways that link the reception of mechanical stress to coherent changes in cardiac contractility.…”

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

“…Notably, NKX2-5 physically interacts with such cooperative partners as GATA4, TBX5, and TBX20, and has been shown to cooperatively regulate the transcription of several essential cardiac target genes, such as troponin I, troponin C, α-actin, and α-myosin heavy chain, 37) and furthermore, mutations in these cooperative partners and cardiac target genes have been causally related to DCM. 8,22,23,[26][27][28][29][30] Hence, it is likely that genetically compromised NKX2-5 confers increased susceptibility to DCM by down-regulating expressions of cardiac target genes.…”

“…Among patients with idiopathic DCM, 25%-50% of the cases have a positive family history, giving rise to the term 'familial' DCM, in contrast to 'sporadic' DCM. 8) Accumulating evidence has demonstrated the genetic origin of idiopathic DCM, and revealed a pattern of autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance in families, of which in over 90% of patients with familial DCM, the pattern of inheritance is autosomal dominant. 8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM.…”

“…8) Accumulating evidence has demonstrated the genetic origin of idiopathic DCM, and revealed a pattern of autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance in families, of which in over 90% of patients with familial DCM, the pattern of inheritance is autosomal dominant. 8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins.…”

“…8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins. 8) Nevertheless, these DCM-causing genes can explain only about one-third of patients and for most genes, the mutational frequency is low, with genetic mutation occurring in < 1% of DCM patients.…”