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A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice
Paige L Snider1, Elizabeth A Sierra Potchanant1, Zejin Sun1
1Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46033, USA.
International Journal of Molecular Sciences
|August 10, 2024
Summary
Barth syndrome (BTHS) cardiomyopathy arises from Tafazzin (TAZ) gene mutations. This study reveals a biphasic progression from mild to severe heart defects in a mouse model, linked to altered metabolic and signaling pathways.
Area of Science:
- Biochemistry
- Genetics
- Cardiology
Background:
- Barth syndrome (BTHS) is characterized by cardiomyopathy, linked to X-linked Tafazzin (TAZ) gene mutations affecting mitochondrial cardiolipin remodeling.
- The precise mechanisms by which TAZ mutations lead to diverse cardiac phenotypes in BTHS are not fully understood.
Purpose of the Study:
- To investigate the genotype-phenotype correlation in BTHS by modeling TAZ mutations in mice.
- To elucidate the temporal changes in cardiac metabolism, mitochondrial function, and signaling pathways contributing to BTHS cardiomyopathy.
Main Methods:
- Generation of a patient-tailored CRISPR/Cas9 knock-in mouse model (Taz) mimicking BTHS.
- Assessment of cardiac metabolic dysfunction, mitochondrial changes, and signaling pathways in juvenile and adult Taz male mice.
Main Results:
- Juvenile Taz males showed mild cardiac dilation with normal ATP and metabolism, but hyperactive p53 and antioxidant pathways.
- Adult Taz males developed chronic heart failure with reduced ATP, suppressed metabolism, cardiac fibrosis, and suppressed p53 and antioxidant pathways.
- A biphasic progression from mild to severe heart phenotype was observed, associated with altered senescence and cardioprotective signaling.
Conclusions:
- Absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy in BTHS.
- The study establishes a genotype-phenotype correlation, highlighting temporal shifts in metabolic and signaling pathways as key drivers of BTHS cardiac progression.
