FVB-Pcca KO/hPCCA*A138T Mice

Catalog Number: C001583

Strain Name: FVB/NJCya-Pccaem1(CAG-hPCCA*A138T)/Cya

Genetic Background: FVB/NJCya

Reproduction: Carrier x Carrier

 

Strain Description

Propionic acidemia (PA) is an autosomal recessive metabolic disorder classified as an organic acidemia. It arises from mutations in the PCCA gene, encoding the α subunit of the mitochondrial enzyme propionyl-CoA carboxylase (PCC), or the PCCB gene, encoding the β subunit, leading to PCC deficiency. PCC, located in the mitochondrial matrix, is composed of six α and six β subunits. Given that PCCB protein relies on PCCA to form a stable complex, patients with PCCA gene defects typically exhibit a deficiency in both subunits, while those with PCCB gene defects also show reduced PCCA protein levels [2]. PA often manifests in the neonatal period, presenting with hyperammonemia, vomiting, feeding difficulties, and hypotonia, potentially progressing to life-threatening metabolic decompensation. Studies have shown that partial knockout of the mouse Pcca gene (the ortholog of the human PCCA gene) can recapitulate the severe symptoms observed in neonatal patients, but these mice usually die within 48 hours of birth [1]. Introduction of a human PCCA gene carrying the hypomorphic A138T mutation into the FVB background strain rescues the phenotype caused by Pcca gene knockout, with hepatic PCC activity approximately 2% of wild-type levels, reproducing the metabolic characteristics and some clinical features of PA patients [2-3].

This strain is a propionic acidemia (PA) disease model generated in the FVB/NJCya background strain using gene editing technology to replace a portion of the mouse Pcca gene sequence with the coding sequence (CDS) of the human PCCA gene carrying the A138T mutation. This model, by simultaneously knocking out the endogenous mouse Pcca gene and expressing the mutant human PCCA gene, mimics the metabolic characteristics of human PA patients and is suitable for investigating the pathogenic mechanisms and therapeutic interventions for propionic acidemia.

Strain Strategy

Using gene editing technology, the sequence from approximately 4kb upstream of exon 1 to part of intron 2 of the mouse Pcca gene was replaced with the "CAG promoter-Kozak-Mutant Human PCCA CDS-WPRE-BGH pA" gene expression cassette. The integrated human PCCA CDS carries the p.A138T (GCT to ACT) mutation.


Application

  • Investigation of the pathogenic mechanisms and therapeutic interventions for propionic acidemia (PA).

 

References
[1]Jiang L, Park JS, Yin L, Laureano R, Jacquinet E, Yang J, Liang S, Frassetto A, Zhuo J, Yan X, Zhu X, Fortucci S, Hoar K, Mihai C, Tunkey C, Presnyak V, Benenato KE, Lukacs CM, Martini PGV, Guey LT. Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia. Nat Commun. 2020 Oct 21;11(1):5339.
[2]Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hofherr SE, Barry MA, Venditti CP. Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum Gene Ther. 2011 Apr;22(4):477-81.
[3]Guenzel AJ, Hofherr SE, Hillestad M, Barry M, Weaver E, Venezia S, Kraus JP, Matern D, Barry MA. Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing. Mol Ther. 2013 Jul;21(7):1316-23.