A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice.
Paige L SniderElizabeth A Sierra PotchanantZejin SunDonna M EdwardsKa-Kui ChanCatalina MatiasJunya AwataAditya ShethP Melanie PrideR Mark PayneMichael RubartJeffrey John BraultMichael Thomas ChinGrzegorz NalepaSimon J ConwayPublished in: International journal of molecular sciences (2024)
Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele ( Taz PM ) that phenocopies BTHS clinical traits. As Taz PM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile Taz PM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile Taz PM hearts. However, adult Taz PM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult Taz PM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.
Keyphrases
- particulate matter
- air pollution
- oxidative stress
- left ventricular
- heart failure
- ejection fraction
- amino acid
- polycyclic aromatic hydrocarbons
- heavy metals
- fatty acid
- crispr cas
- genome wide
- multiple sclerosis
- water soluble
- case report
- dna damage
- aortic stenosis
- signaling pathway
- endothelial cells
- cell death
- acute myocardial infarction
- atrial fibrillation
- diabetic rats
- genome editing
- small molecule
- transcatheter aortic valve replacement
- cell proliferation
- hypertrophic cardiomyopathy
- risk assessment
- aortic valve
- coronary artery disease
- metabolic syndrome
- gene expression
- endoplasmic reticulum stress
- smoking cessation
- anti inflammatory
- single cell
- wild type