Disease relevance of PCCA

• Mutations of the PCCA (alpha subunit) or PCCB (beta subunit) gene cause the inherited metabolic disease, propionic acidemia [1].
• OBJECTIVE: To analyze a single center's 14-year experience with 62 consecutive patients with hilar (HCCA) and peripheral (PCCA) cholangiocarcinomas [2].
• In all cases, the levels of mRNA were lower in colorectal cancers than in normal mucosae, the decrease being always more marked for PCCB than for PCCA [3].

High impact information on PCCA

• PCC consists of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively [4].
• These data suggest that the level of PCCA expression in fibroblasts does not normally limit PCC holoenzyme activity or propionate flux [5].
• Both clones reconstitute propionate flux to normal levels in fibroblasts from patients genetically deficient in PCCA (pccA) [5].
• The second encodes a chimera composed of the mitochondrial leader sequence of human methylmalonyl CoA mutase and the mature PCCA protein [5].
• A postnatal, liver-specific PCC expression via a transgene in a far lower level than that in wild-type liver, allowed PCCA(-/-) mice to survive the newborn and early infant periods, preventing a lethal fit of ketoacidosis (SAP(+)PCCA(-/-) mice) [6].

Chemical compound and disease context of PCCA

• Having observed a high biotin content in colon mucosae and a low content in colorectal-cancer cells, we then studied the transcription levels of PCCA and PCCB genes in 9 colorectal cancers and the corresponding mucosae [3].

Biological context of PCCA

• By use of a panel of somatic mouse-human hybrids, the human gene encoding the alpha polypeptide (PCCA) was localized to chromosome 13, while the gene encoding the beta polypeptide (PCCB) was assigned to chromosome 3 [7].
• More than 24 mutations have been found in the PCCA gene in patients with PA, among them 14 missense mutations and one in-frame deletion, for which the precise molecular effect is unknown [8].
• The PCCA protein (alpha subunit) is responsible for the formation of carboxybiotin upon hydrolysis of ATP and contains a C-terminal biotin-binding domain and a biotin carboxylase domain, defined by homology with other biotin-dependent carboxylases, some of them characterized structurally [8].
• In this study, we have established the pathogenicity of 11 PCCA mutations (10 missense and an in-frame deletion) by expression studies in deficient fibroblasts and in a cell-free in vitro system, and analyzed the effect of each mutation on PCC activity, protein stability and domain structure [8].
• We have found a highly heterogenous spectrum of PCCA mutations, most of the PCCA deficient patients are homozygous carrying a unique genotype [9].

Anatomical context of PCCA

• We describe cDNA clones expressing human PCCA and complementation of the genetic defect in pccA fibroblasts by DNA-mediated gene transfer [5].

Associations of PCCA with chemical compounds

• Isolation of cDNA clones coding for the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA and PCCB genes [7].
• Assignment of the human gene propionyl coenzyme A carboxylase, alpha-chain, (PCCA) to chromosome 13q32 by in situ hybridization [10].
• Mutations in the PCCA or PCCB genes coding for alpha and beta subunits of propionyl CoA carboxylase can cause propionic acidemia [11].

Other interactions of PCCA

• Here, we report NMR studies of two duplexes, 5'GGU GGA GGCU/PCCA AAG CCG5' (replacing the UG pair with a UA closing pair) and 5'GGU GAA GGCU/PCCG AAG CCG5' (replacing the middle GA pair with an AA pair) [12].

Analytical, diagnostic and therapeutic context of PCCA

• These factors may have important implications for the rational design of somatic gene therapy for PCCA deficiency [5].
• Mutations in both the PCCA and PCCB genes have been identified by sequencing either RT-PCR products or amplified exonic fragments, the latter specifically for the PCCB gene for which the genomic structure is available [13].
• The disease-free survival rates for HCCA and PCCA were 85% (+/-10%) and 77% (+/-9%) at 1 year; 18% (+/-11%) and 41% (+/-12%) at 3 years; and 18% (+/-11%) and 41% (+/-12%) at 5 years, respectively [2].
• Two mutations in the PCCA gene detected in homozygous patients and involving consensus splice sequences (IVS21+3del4 and IVS22-2A>G) were shown to produce some normal splicing in patients' cells, at very low levels, which were quantitated by real-time PCR methods, and which presumably are sufficient to moderate the phenotype [14].

References