Cardiomyopathy and Myosin Studies

Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T

This study connects genotype, phenotype, and drug response in dilated cardiomyopathy using molecular mechanism-based computational and experimental approaches for a troponin T mutation.

SMYD1-mediated Mono-Methylation of Lysine K35 of the sarcomeric Myosin Heavy Chain (MHC) is fundamental for thick filament assembly in zebrafish and human iPSC-derived cardiomyocytes

This study identifies SMYD1-mediated mono-methylation of Myh K35 as essential for thick filament assembly in zebrafish and human cardiomyocytes.

Activated fibroblasts drive cellular interactions in end-stage pediatric hypertrophic cardiomyopathy

This study identifies distinct cellular processes in end-stage pediatric HCM using single-nucleus RNA sequencing, highlighting activated fibroblasts and stressed cardiomyocytes.

Cardiac stress leads to regulation of Filamin C dimerisation via an ancient phosphorylation-modulated interaction with HSPB7

The paper investigates how cardiac stress regulates Filamin C dimerisation through phosphorylation-modulated interactions with HSPB7, revealing evolutionary conservation of this mechanism.

FGF12 Modulates Cardiomyocyte Hypertrophy by Inhibiting GATA4-ERK1/2 Phosphorylation Through Altered Intracellular Localization

This study identifies FGF12's role in cardiomyocyte hypertrophy by inhibiting GATA4-ERK1/2 phosphorylation through altered nuclear localization in HCM.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction

This study shows Omecamtiv mecarbil and Mavacamten target the same myosin pocket but have antagonistic effects on heart contraction through structural and simulation analyses.

Lipid metabolism drives allele-specific early-stage hypertrophic cardiomyopathy

This study identifies allele-specific metabolic differences in HCM mouse models, linking lipid metabolism to early-stage cardiac dysfunction.

The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings

This paper estimates the penetrance of rare variants in cardiomyopathy genes using cross-sectional data from genetic testing, finding substantial penetrance for dominant cardiomyopathies and variant-specific differences.

Top-down Proteomics of Myosin Light Chain Isoforms Define Chamber-Specific Expression in the Human Heart

The paper uses top-down proteomics to analyze MLC-1 and -2 isoform expression in human heart chambers, revealing chamber-specific patterns and a novel PTM.

Multiplexed functional assessments of MYH7 variants in human cardiomyocytes at scale

This study uses hiPSC-derived cardiomyocytes to assess MYH7 variants' effects, showing pathogenic variants reduce protein abundance and cell survival.

Age and Sex Differences in the Genetics of Cardiomyopathy

This study identifies genetic differences between pediatric and adult cardiomyopathy, finding more constrained variants in childhood cases and female patients.

Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects

The paper identifies heterozygous missense variants in ACTC1 as the cause of distal arthrogryposis with congenital heart defects in five families.

Multi-scale models reveal hypertrophic cardiomyopathy MYH7 G256E mutation drives hypercontractility and elevated mitochondrial respiration

This study investigates the effects of the MYH7 G256E mutation on myosin function across multiple scales, finding increased hypercontractility and mitochondrial respiration.

Differences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study

The paper examines cardiac mechanics in genetically at-risk first-degree relatives of DCM patients, finding that older relatives with variants of uncertain significance or pathogenic variants have reduced global longitudinal strain.

Transcriptome Data Analysis of Primary Cardiomyopathies Reveals Perturbations in Arachidonic Acid Metabolism

This study identifies perturbations in arachidonic acid metabolism across primary cardiomyopathies using RNA-seq data and gene set analysis.

Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

This study shows that ablating PALLD in adult hearts causes dilated cardiomyopathy with intercalated disc abnormalities and fibrosis, suggesting PALLD's essential role in cardiac function.

Genetic Inactivation of Beta-Catenin Attenuates and Its Activation Aggravates Desmoplakin Cardiomyopathy

This study shows that genetic inactivation of beta-catenin improves desmoplakin cardiomyopathy by restoring oxidative phosphorylation gene expression, while its activation worsens the condition.

Cardiomyocyte apoptosis contributes to contractile dysfunction in stem cell model of MYH7 E848G hypertrophic cardiomyopa-thy

This study shows that MYH7 E848G mutation causes cardiomyocyte apoptosis and contractile dysfunction in a stem cell model of HCM, independent of p53.

Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy

The paper develops a signaling network model to investigate genotype-to-phenotype mechanisms in familial cardiomyopathy, showing it can predict experimental outcomes and suggest therapeutic strategies.

Nanobodies combined with DNA-PAINT super-resolution reveal a staggered titin nano-architecture in flight muscles

The paper uses nanobodies and DNA-PAINT to show that Drosophila titin homologs Sallimus and Projectin are staggered in flight muscle sarcomeres.

Evaluating a communication aid for return of genetic results in families with hypertrophic cardiomyopathy: A randomized controlled trial

This paper evaluates a communication aid for returning genetic results in HCM families, finding no significant difference in communication effectiveness but noting higher knowledge scores in the intervention group.

A Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1-mediated Trabeculation Cessation

This study identifies a CHD4 missense mutation causing ventricular noncompaction by repressing ADAMTS1-mediated trabeculation cessation in mice and humans.

Loss-of-Function FLNC Variants are Associated with Arrhythmogenic Cardiomyopathy Phenotypes when Identified through Exome Sequencing of a General Clinical Population

The paper identifies FLNC loss-of-function variants in a clinical population and finds they are associated with increased odds of arrhythmogenic cardiomyopathy phenotypes.

Variants identify sarcomere inter-protein contacts distinguishing inheritable cardiac muscle diseases

The paper identifies co-domains in sarcomere proteins that distinguish cardiac diseases by analyzing SNVs and their impact on inter-protein contacts using a neural/Bayes network model.

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

This study uses whole-genome sequencing to identify regulatory and novel genic variants contributing to childhood cardiomyopathy.

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

The paper investigates how mono- and bi-allelic ACTN2 mutations cause cardiomyopathy through distinct mechanisms using patient-derived iPSC-cardiomyocytes and CRISPR-Cas9 editing.

Mutations in CSRP3/MLP, a Z-disc associated gene are functionally associated with dilated cardiomyopathy in Indian population

The paper identifies and functionally characterizes CSRP3 variants in Indian DCM patients, showing reduced protein levels and disrupted interactions, suggesting a role in DCM pathogenesis.

Direct detection of the myosin super-relaxed state and interacting heads motif in solution

The paper uses TR-FRET to directly measure the correlation between the interacting-heads motif (IHM) and super-relaxed state (SRX) in myosin, finding that SRX is more stabilized by mavacamten than IHM.

Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

This study examines the clinical impact of rare variants in HCM-associated genes in the UK Biobank, finding that pathogenic variants are linked to increased cardiovascular risk and subclinical phenotypes, while non-pathogenic variants show minimal effect.

Analysis of HCM in an understudied population reveals a new mechanism of pathogenicity

The paper identifies a frameshift variant in MYH7 associated with HCM in an Egyptian cohort, revealing a new pathogenic mechanism involving distal PTC escape from NMD.