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Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy.

ABSTRACT: Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM.Sixty-two genotyped individuals in families with sarcomeric DCM underwent clinical evaluation including strain echocardiography. The group included 12 subclinical DCM mutation carriers with normal cardiac dimensions and left ventricular ejection fraction (LVEF ?55%), 21 overt DCM subjects, and 29 related mutation (-) normal controls. Results were compared with a previously characterized cohort of 60 subclinical HCM subjects (sarcomere mutation carriers without left ventricular hypertrophy). Systolic myocardial tissue velocity, longitudinal, circumferential, and radial strain, and longitudinal and radial strain rate were reduced by 10%-23% in subclinical DCM mutation carriers compared with controls (P<0.001 for all comparisons), after adjusting for age and family relations. No significant differences in diastolic parameters were identified comparing the subclinical and control cohorts. The opposite pattern of contractile abnormalities with reduced diastolic but preserved systolic function was seen in subclinical HCM.Subtle abnormalities in systolic function are present in subclinical DCM mutation carriers, despite normal left ventricular size and ejection fraction. In contrast, impaired relaxation and preserved systolic function appear to be the predominant early manifestations of sarcomere mutations that lead to HCM. These findings support the theory that the mutation's intrinsic impact on sarcomere function influences whether a dilated or hypertrophic phenotype develops.

SUBMITTER: Lakdawala NK

PROVIDER: S-EPMC3646896 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy.

Lakdawala Neal K NK Thune Jens J JJ Colan Steven D SD Cirino Allison L AL Farrohi Faranak F Rivero Jose J McDonough Barbara B Sparks Elizabeth E Orav E J EJ Seidman J G JG Seidman Christine E CE Ho Carolyn Y CY

Circulation. Cardiovascular genetics 20120904 5

<h4>Background</h4>Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM.<h4>Methods and results</h4>Sixty-two genotyped individuals in families wi ...[more]

PMID: 22949430

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Project description:Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome-wide scan with microsatellite markers and genetic linkage analysis in a 4-generation family inflicted with autosomal-dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1-q13.3, a 4.77-cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2-point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole-exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7. Add, the E144X-mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

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Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy.

Publications

Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy.

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