Venditti, Charles (NHGRI)
Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by mutations in either Propionyl-CoA carboxylase alpha (PCCA) or Propionyl-CoA carboxylase beta (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 recapitulate the human clinical phenotype of severe propionic acidemia caused by PCCB deficiency, namely neonatal lethality and increased propionyl-CoA derived metabolites. These new PCCB alleles are the first described and can be used to model the spectrum of clinically important features of PA, and support testing of new treatments, including adeno-associated virus (AAV) gene therapy, mRNA therapy, genome editing, base editing, mRNA editing, small molecules, enzyme replacement therapy, and microbiome targeted therapies.
These alleles will be useful to study new therapies for PA.
These new mouse models recapitulate the severe mutations seen in patients and do not rely upon gene replacement. Carriers of these new PCCB mutations are fully fertile and can be easily bred and genotyped using fluorescent or conventional PCR.