Exploring GIs in a Human Cell Line:
Generating A Mitochondrial Network in Health and Disease
This project is a collaboration with the lab of Jason Moffat, Genetics and Genome Biology at Sick Kids
People
Sanna Masud
Barth syndrome (BTHS) is a multi-systemic, X-linked rare congenital heart disease and is caused by mutation of the TAFAZZIN (TAZ) gene. TAZ encodes a highly conserved transacylase that remodels immature forms of cardiolipin into mature cardiolipin, the hallmark phospholipid of the inner mitochondrial membrane. BTHS patients have complex clinical presentation, exhibiting a diverse spectrum of phenotypes and disease severity, making it difficult to both diagnose and manage with no disease-specific therapeutics available. This phenotypic variance observed in BTHS patients suggests that there are important relationships between mutant TAZ and other genes involved in mitochondrial/cellular function, also known as genetic interactions or genetic modifiers, that mediate expressed phenotypes. This project leverages genome-scale pooled CRISPR loss of function screens in human cell models to interrogate the genetic dependencies of TAZ and identify suppressors as a therapeutic opportunity for BTHS, and other conditions that are caused by aberrant cardiolipin. To further understand TAZ and the pleiotropic nature of BTHS/ other mitochondrial diseases, we have also performed ~100 mitochondrial query genetic interaction screens in the HAP1 model to generate a comprehensive mitochondrial profile similarity network, Mitonet.
