Mitochondrial protein synthesis requires the charging of mt-tRNAs with their cognate amino acids. This is accomplished by nuclear DNA-encoded mitochondrial aminoacyl-tRNA synthetases (ARS2), with the exception of glutaminyl mt-tRNA (mt-tRNAGln), which is charged by an indirect pathway involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects in the mitochondrial protein synthesis machinery cause a broad spectrum of mitochondrial disorders, often with a fatal outcome. In this study, we describe nine patients from five families with genetic defects in each of the GatCAB complex subunits. Our findings show that defects in the GatCAB complex result in a lethal metabolic cardiomyopathy syndrome. Functional studies on patient fibroblasts and muscle biopsies revealed variable combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Our study completes a decade of investigations, started with the discovery of pathogenic variants in DARS2 causing a leukoencephalopathy syndrome, now linking all mitochondrial aminoacylation genes to human disorders.
