Patient-Tailored Mouse Genome Editing Recapitulates Hematopoietic And Systemic Manifestations Of Barth Syndrome

Barth syndrome (BTHS; OMIM# 302060) is an X-linked disorder of neutropenia, cardiomyopathy and muscular weakness due to mitochondrial dysfunction secondary to inherited tafazzin (TAZ) mutations. Neutropenia occurs in the majority of BTHS patients, leading to high risk of recurrent life-threatening bacterial infections. The etiology of the G-CSF-responsive neutropenia in BTHS is incompletely understood and appears to reflect impaired granulopoiesis. Long-term risk of myelodysplasia (MDS) in BTHS individuals requiring chronic G-CSF therapy is unknown due to the rarity of the disorder; further, genotype-phenotype correlations between the severity of neutropenia and TAZ mutations remain to be elucidated. Genetic Taz knockout is embryonic lethal in the mouse. Therefore, a genetic BTHS mouse model is urgently needed to improve our mechanistic understanding of this disease and develop clinical studies based on preclinical evidence.