Pcca-flox Mouse

Pcca, the gene encoding the alpha subunit of propionyl-CoA carboxylase, is crucial for the function of this enzyme. Propionyl-CoA carboxylase is involved in the metabolism of several amino acids, odd-chain fatty acids, and cholesterol side-chains, playing a significant role in normal cellular metabolism [1].

A study showed that the PCCA c.1285-1416A>G variation activates a pseudoexon. This activation disrupts normal gene expression, leading to a deficiency of the propionyl-CoA carboxylase enzyme and causing the severe metabolic disorder propionic acidemia. However, blocking this region of regulation with splice-switching antisense oligonucleotides can restore normal splicing and rescue enzyme activity in patient fibroblasts and in a CRISPR-created cellular model. Moreover, blocking the inclusion of the non-activated wild-type pseudoexon can increase both PCCA and PCCB protein levels, enhancing the activity of the heterododecameric enzyme, which could be a potential treatment strategy for propionic acidemia [1].

In conclusion, Pcca is essential for the proper function of propionyl-CoA carboxylase in normal cellular metabolism. The discovery of the role of pseudoexon activation and the potential treatment strategy through splice-switching antisense oligonucleotides in Pcca-related propionic acidemia provides new insights into the treatment of this metabolic disorder.