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Compound mutations in HRC and MYBPC3 synergistically increase cardiac pathogenicity

ABSTRACT: Compound mutations in HRC and MYBPC3 synergistically increase cardiac pathogenicity

PROVIDER: PRJNA1174185 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31031984_1.fastq.gz	Fastqsanger.gz
	SRR31031984_2.fastq.gz	Fastqsanger.gz
	SRR31031985_1.fastq.gz	Fastqsanger.gz
	SRR31031985_2.fastq.gz	Fastqsanger.gz
	SRR31031986_1.fastq.gz	Fastqsanger.gz

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Compound mutations in HRC and MYBPC3 synergistically increase cardiac pathogenicity

Project description:Hypertrophic cardiomyopathy (HCM) and arrhythmia are two leading causes of sudden cardiac death (SCD). A 25-base pair deletion in intron 32 of cardiac myosin binding protein C (MYBPC3Δ25bp) results in cardiomyopathies in 6% of South Asians. Within this population, another compounded genetic variant of a Serine to Alanine mutation in the 96th codon of HRC (HRCS96A) is present with frequencies of 48% (heterozygous) and ~16% (homozygous), resulting in a higher incidence of sudden death in dilated cardiomyopathy (DCM). To elucidate the pathogenicity of impaired Ca2+-cycling and arrhythmias by the HRCS96A polymorphism in the setting of altered sarcomere function instrumented by the MYBPC3Δ25bp variant. Using transgenic mouse models, we studied the effects of the MYBPC3Δ25bp and the HRC mutation (murine S81A) alone and together (double variant, DV). Electrocardiogram tracing of DV mice also indicated increased stress-induced arrhythmias, such as ventricular tachycardia, after caffeine and epinephrine administration. In vitro, IonOptix experiments using freshly isolated adult cardiomyocytes revealed DV mice significantly decreased fractional shortening, Ca2+ transient amplitude, and higher number of after-contraction. When challenged with transverse aortic constriction (TAC), the DV mice also displayed more severe systolic and diastolic dysfunction as measured by echocardiography. In subsequent RNA sequencing studies, compared to the non-transgenic controls, the DV mice had significantly more dysregulated genes than the single-variant mice. A perturbagen screen followed the RNA sequencing study to predict small molecules could revert these pathological gene signatures in the DV mice. These studies highlight the increased pathogenicity of compound variants in calcium handling and sarcomeric genes, as evidenced by increased cardiac dysfunction at baseline and post-TAC and increased pathological gene dysregulation in the double variant mice.

2024-10-24 | GSE279737 | GEO

Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

Project description:Pathogenic variants in MYBPC3 (myosin-binding protein C3) are the leading cause of genetic hypertrophic cardiomyopathy (HCM). Currently, there is no specific and effective treatment for this disease. Base editing is an emerging modality for treating monogenic diseases; however, its effect on MYBPC3 cardiomyopathy remains unexplored. Mybpc3-R946X/R946X mice developed early-onset left ventricular hypertrophy, systolic dysfunction, ventricular dilatation, and arrythmias. SpRY-ABEmax inefficiently corrected the Mybpc3-R946X mutation. In contrast, SpRY-ABE8e increased the efficiency by 3.6-fold and retained low level off-target editing. In vivo administration of SpRY-ABE8e efficiently corrected Mybpc3-R946X mutation in cardiomyocytes and prevented heart function decline, hypertrophic cardiomyopathy, and ventricular dysfunction. The therapeutic efficacy of SpRY-ABE8e-mediated gene correction surmounted AAV-mediated Mybpc3 gene replacement.Our study unveiled the immense potential of base editing to treat fatal inherited cardiomyopathies and opened a new avenue for the therapeutic managements of inherited cardiac diseases.

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EXCEED Study HRC imputation

Project description:EXCEED samples imputed to HRC reference panel using Michigan Imputation server

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Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A

Project description:Induced pluripotent stem cells (iPSCs) were generated from a patient with severe, early onset hypertrophic cardiomyopathy due to pathogenic (c.506-1G>A) and low penetrance pathogenic (c.442G>A) variants in MYBPC3 in trans (i.e. MYBPC3 biallelic patient). Healthy control (WTC11, Coriell repository) iPSCs were used as reference. iPSCs were differentiated into cardiomyocytes for transcriptome analysis and assessment of the c.442G>A variant on MYBPC3 splicing.

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Transcriptome study of MYBPC3 loss of function mutations

Project description:Transcriptome study of MYBPC3 loss of function mutations

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ALV-J and REV synergistically increase the accumulation of miRNAs

Project description:ALV-J and REV synergistically increase the accumulation of miRNAs

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Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in hypertrophic cardiomyopathy mice

Project description:The study investigates the effect of a heterozygous MYBPC3 mutation combined with Western diet feeding on protein expression in a HCM mouse model. Hypertrophic cardiomyopathy (HCM) is the most common inherited genetic heart disease, characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction. It is generally accepted that HCM is caused by mutations in genes encoding sarcomere proteins (e.g. MYBPC3, MYH7). However, not all mutation carriers will develop HCM and, moreover, phenotypical variation in terms of clinical presentation is large. The phenotypical expression of HCM thus requires additional disease modifiers on top of a sarcomere gene mutation. Clinical reports identify obesity and related comorbidities (diabetes, hyperlipidemia, hypertension) as a major factor contributing to disease expression and severity. We aimed to mimic this situation in a HCM mouse model by feeding a Western diet (8 weeks) to mice carrying a heterozygous mutation in MYBPC3. These heterozygous mice are phenotype negative under normal conditions, but developed cardiac dysfunction and hypertrophy upon Western diet feeding. The main goal of this proteomic screening is to identify clusters of proteins and pathways that are down/upregulated specifically in the left ventricle of mice suffering from a mutation and Western diet feeding. Also, we are interested in protein expression differences caused solely by mutation or Western diet. Group 1 are Wild type mice that received normal chow; group 2 are heterozygous mice that received normal chow; group 3 are Wild type mice that received a Western diet; group 4 are heterozygous mice that received a Western diet.

2023-10-01 | PXD043345 | Pride

eMERGE Network Phase III: HRC Imputed Array Data of 85,000+ Participants

Project description:eMERGE Network Phase III: HRC Imputed Array Data of 85,000+ Participants

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eMERGE Network Phase III: HRC Imputed Array Data of 85,000+ Participants

Project description:eMERGE Network Phase III: HRC Imputed Array Data of 85,000+ Participants

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