Improved Propionyl-CoA Carboxylase Alpha (PCCA) Alleles in Mouse Models for the Study of Propionic Acidemia (PA) and its Potential Treatments

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by mutations in either PCCA or PCCB. The products of these genes form the alpha and beta subunits of the enzyme propionyl-Co A carboxylase (PCC), a critically important mitochondrial enzyme involved in the catabolism of branched chain amino acids. NHGRI scientist have developed new mouse models that more closely mimic the nature of mutations seen in patients, such as missense mutations, small insertion and deletions, splicing defects, and frameshift changes. Also, there are no rescue transgenes and the alleles are at the Pcca locus, making breeding of the mice easier than if a rescue transgene was required. The new PCCA mutations generated should be useful to model the spectrum of clinically important postnatal features of PA, such as dietary sensitivity to precursors, growth failure, metabolic instability, cardiomyopathy, and afford testing of new treatments, including adeno-associated virus (AAV) gene therapy, mRNA therapy, genome editing, base editing, mRNA editing, small molecules and enzyme replacement therapy.