A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice

• Published in: International journal of molecular sciences 2024-08, Vol.25 (15), p.8201
• Main Authors: Snider, Paige L, Sierra Potchanant, Elizabeth A, Sun, Zejin, Edwards, Donna M, Chan, Ka-Kui, Matias, Catalina, Awata, Junya, Sheth, Aditya, Pride, P Melanie, Payne, R Mark, Rubart, Michael, Brault, Jeffrey J, Chin, Michael T, Nalepa, Grzegorz, Conway, Simon J
• Format: Article
• Language: English
• Subjects: Acyltransferases - genetics; Adenosine triphosphate; Amino acids; Animals; Barth Syndrome - genetics; Barth Syndrome - metabolism; Barth Syndrome - pathology; Biosynthesis; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathy; CRISPR; Disease Models, Animal; Enzymes; Gene mutations; Genetic aspects; Genomes; Genotype & phenotype; Heart diseases; Heart failure; Humans; Male; Mice; Mitochondria; Muscle proteins; Mutation; Neutropenia; Neutrophils; Patients; Phenotype; Point Mutation; Proteins; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158201

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored knock-in mouse allele ( ) that phenocopies BTHS clinical traits. As males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile 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 hearts. However, adult 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 hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.