Functional Analysis of Two Novel Mutations in TWIST1 Protein Motifs Found in Ventricular Septal Defect Patients

Deng, Xiaopeng; Pan, Hong; Wang, Jing; Wang, Binbin; Cheng, Zhi; Cheng, Longfei; Zhao, Liang; Li, Hui; Ma, Xu

doi:10.1007/s00246-015-1202-9

Cited by 5 publications

(1 citation statement)

References 42 publications

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“…Due to advances in heart failure therapy through pacemaker based cardiac resynchronization therapy, the assessment of cardiac dyssynchrony based on imaging has gained increasing attention [ 5 , 6 ]. Dyssynchrony can be quantified from electrocardiograms (ECG), echocardiography and cardiovascular magnetic resonance imaging (CMR) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Left ventricular synchrony, torsion, and recoil mechanics in Ebstein's anomaly: insights from cardiovascular magnetic resonance

Steinmetz

Usenbenz

Kowallick

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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BackgroundDisease progression and heart failure development in Ebstein’s Anomaly (EA) of the tricuspid valve is characterized by both right and left ventricular (LV) deterioration. The mechanisms underlying LV dysfunction and their role in heart failure development are incompletely understood. We hypothesized that LV dyssynchrony and impaired torsion and recoil mechanics induced by paradoxical movement of the basal septum may play a role in heart failure development.Methods31 EA patients and 31 matched controls underwent prospective cardiovascular magnetic resonance (CMR). CMR feature tracking (CMR-FT) was performed on apical, midventricular and basal short-axis and 4D–volume analysis was performed using three long-axis views and a short axis cine stack employing dedicated software. Circumferential uniformity ratio estimates (CURE) time-to-peak-based circumferential systolic dyssynchrony index (C-SDI), 4D volume analysis derived SDI (4D–SDI), torsion (Tor) and systolic (sysTR) and diastolic torsion rate (diasTR) were calculated for the LV. QRS duration, brain natriuretic peptide, NYHA and Total R/L-Volume Index (R/L Index) were obtained.ResultsEA patients (31.5 years; controls 31.4 years) had significantly longer QRS duration (123.35 ms ± 26.36 vs. 97.33 ms ± 11.89 p < 0.01) and showed more LV dyssynchrony (4D–SDI 7.60% ± 4.58 vs. 2.54% ± 0.62, p < 0.001; CURE 0.77 ± 0.05 vs. 0.86 ± 0.03, p < 0.001; C-SDI 7.70 ± 3.38 vs. 3.80 ± 0.91, p = 0.001). There were significant associations of LV dyssynchrony with heart failure parameters and QRS duration. Although torsion and recoil mechanics did not differ significantly (p > 0.05) there was an association of torsion and recoil mechanics with dyssynchrony parameters CURE (sysTR r = −0.426; p = 0.017, diasTR r = 0.419; p = 0.019), 4D–SDI (sysTR r = 0.383; p = 0.044) and C-SDI (diasTR r = −0.364; p = 0.044).ConclusionsEA is characterized by LV intra-ventricular dyssynchrony, which is associated with heart failure and disease severity parameters. Markers of dyssynchrony can easily be quantified from CMR-FT, and may have a role in the assessment of altered cardiac function, carrying potential management implications for EA patients.Electronic supplementary materialThe online version of this article (10.1186/s12968-017-0414-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Left ventricular synchrony, torsion, and recoil mechanics in Ebstein's anomaly: insights from cardiovascular magnetic resonance

Steinmetz

Usenbenz

Kowallick

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

Wang

Guo

et al. 2016

Pediatr Cardiol

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As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 loss-of-function mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF.

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Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction

et al. 2016

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Cardiovascular diseases (CVDs) are the leading causes of death worldwide and represent a substantial economic burden on public health care systems. Epigenetic markers have potential as diagnostic markers before clinical symptoms have emerged, and as prognostic markers to inform the choice of clinical intervention. In this study, we performed an epigenome-wide association study (EWAS) for CVDs, to identify disease-specific alterations in DNA methylation. CpG methylation in blood samples from the northern Sweden population health study (NSPHS) (n = 729) was assayed on the Illumina Infinium HumanMethylation450 BeadChip. Individuals with a history of a CVD were identified in the cohort. It included individuals with hypertension (N = 147), myocardial infarction (MI) (N = 48), stroke (N = 27), thrombosis (N = 22) and cardiac arrhythmia (N = 5). Differential DNA methylation was observed at 211 CpG-sites in individuals with a history of MI (q <0.05). These sites represent 196 genes, of which 42 have been described in the scientific literature to be related to cardiac function, cardiovascular disease, cardiogenesis and recovery after ischemic injury. We have shown that individuals with a history of MI have a deviating pattern of DNA methylation at many genomic loci of which a large fraction has previously been linked to CVD. Our results highlight genes that might be important in the pathogenesis of MI or in recovery. In addition, the sites pointed out in this study can serve as candidates for further evaluation as potential biomarkers for MI.

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Functional Analysis of Two Novel Mutations in TWIST1 Protein Motifs Found in Ventricular Septal Defect Patients

Cited by 5 publications

References 42 publications

Left ventricular synchrony, torsion, and recoil mechanics in Ebstein's anomaly: insights from cardiovascular magnetic resonance

Left ventricular synchrony, torsion, and recoil mechanics in Ebstein's anomaly: insights from cardiovascular magnetic resonance

HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction

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