Modeling Inherited Methylmalonic Acidemia Using Isogenic Human Induced Pluripotent Stem Cell-Derived Hepatocytes with...

Isolated methylmalonic acidemia (MMA) is an autosomal recessive disorder that increases methylmalonic acid by affecting the metabolism of propionyl-CoA. Mutations in multiple genes cause MMA, however, those in methylmalonyl-CoA mutase ( MMUT ) are most common. MMUT is an isomerase that converts methylmalonyl-CoA to succinyl-CoA, a key tricarboxylic acid (TCA) cycle intermediate. The defects in these metabolic processes disproportionately affect hepatocytes in patients with MMA. We performed gene editing in human induced pluripotent stem cells (hiPSCs) to generate loss-of-function mutations within MMUT . Hepatocytes derived from these iPSCs recapitulate key aspects of methylmalonic acidemia, providing a new model of MMA.