# Mechanisms and Treatment of Cardiac and Skeletal Muscular Dysfunction in Barth Syndrome

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $416,007

## Abstract

PROJECT SUMMARY
Barth syndrome (BTHS) is a rare, frequently fatal, mitochondrial disease caused by recessive loss-of-function
mutations in the gene TAZ, which encodes tafazzin. Tafazzin is a nuclear-encoded transferase that is trafficked
to the inner mitochondrial membrane where it remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL).
A critical phospholipid, CL is involved in maintenance of mitochondrial membrane fluidity, osmotic stability, and
efficient respiratory chain function. In BTHS patients, improper MLCL:CL ratios result in decreased mitochondrial
energy production and cardioskeletal myopathy. Although deficient CL remodeling exists in all BTHS patients,
there are considerable differences in disease progression and clinical presentation and the basis for these
differences remains obscure. These differential clinical outcomes combined with the high variability in the
location and severity of TAZ mutations suggest that tafazzin possesses uncharacterized functions that may
involve interactions with unidentified proteins to influence BTHS and common heart failure presentation as well.
In order to define these novel mechanisms, we propose to 1) evaluate overall protein expression profiles as well
as mitochondrial morphology, turnover, and function in human BTHS patient induced pluripotent stem cells
(iPSCs) differentiated into cardiomyocytes (CMs) and skeletal myotubes (SkMs) using both standard culture
systems and biomimetic microenvironments, 2) compare iPSC-CM and -SkM phenotypes to human clinical
skeletal muscle and cardiac functional, metabolic and energetic indices, and 3) design human native and mutant
tafazzin constructs with missense mutations to evaluate alterations in tafazzin protein localization and complex
binding patterns. TAZ gene replacement and subsequent analyses will confirm that the observed effects are
caused by tafazzin deficiencies. The in vitro work will be complemented by in vivo BTHS mouse model analyses
and human data from an ongoing clinical study. In combination, these models will provide valuable platforms for
defining disease mechanisms and testing pre-clinical gene therapy. We hypothesize that evaluation of functional
abnormalities, identification of tafazzin protein complex binding partners and their impact on expression profiles
in mitochondria from BTHS iPSCs differentiated into CMs and SkMs representing a variety of distinct TAZ
mutations and a BTHS mouse model will reveal novel roles for tafazzin. As decreased TAZ expression has been
associated with a variety of non-BTHS heart disease states and CL abnormalities have been detected in a range
of disorders, mechanistic knowledge gained from this study has great potential to improve our general
understanding of and provide novel therapeutic targets for a wide range of health concerns that stretch well
beyond BTHS.

## Key facts

- **NIH application ID:** 10401946
- **Project number:** 5R01HL136759-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** CHRISTINA A. PACAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,007
- **Award type:** 5
- **Project period:** 2021-02-06 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401946

## Citation

> US National Institutes of Health, RePORTER application 10401946, Mechanisms and Treatment of Cardiac and Skeletal Muscular Dysfunction in Barth Syndrome (5R01HL136759-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401946. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*