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Gene Review

PCCA  -  propionyl CoA carboxylase, alpha polypeptide

Homo sapiens

Synonyms: PCCase subunit alpha, Propanoyl-CoA:carbon dioxide ligase subunit alpha, Propionyl-CoA carboxylase alpha chain, mitochondrial
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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


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


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].


  1. Correction of the metabolic defect in propionic acidemia fibroblasts by microinjection of a full-length cDNA or RNA transcript encoding the propionyl-CoA carboxylase beta subunit. Lamhonwah, A.M., Leclerc, D., Loyer, M., Clarizio, R., Gravel, R.A. Genomics (1994) [Pubmed]
  2. Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Madariaga, J.R., Iwatsuki, S., Todo, S., Lee, R.G., Irish, W., Starzl, T.E. Ann. Surg. (1998) [Pubmed]
  3. Strong decrease in biotin content may correlate with metabolic alterations in colorectal adenocarcinoma. Cherbonnel-Lasserre, C.L., Linares-Cruz, G., Rigaut, J.P., Sabatier, L., Dutrillaux, B. Int. J. Cancer (1997) [Pubmed]
  4. High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Ravn, K., Chloupkova, M., Christensen, E., Brandt, N.J., Simonsen, H., Kraus, J.P., Nielsen, I.M., Skovby, F., Schwartz, M. Am. J. Hum. Genet. (2000) [Pubmed]
  5. Cloning of functional alpha propionyl CoA carboxylase and correction of enzyme deficiency in pccA fibroblasts. Stankovics, J., Ledley, F.D. Am. J. Hum. Genet. (1993) [Pubmed]
  6. Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. Miyazaki, T., Ohura, T., Kobayashi, M., Shigematsu, Y., Yamaguchi, S., Suzuki, Y., Hata, I., Aoki, Y., Yang, X., Minjares, C., Haruta, I., Uto, H., Ito, Y., Müller, U. J. Biol. Chem. (2001) [Pubmed]
  7. 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. Lamhonwah, A.M., Barankiewicz, T.J., Willard, H.F., Mahuran, D.J., Quan, F., Gravel, R.A. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  8. Functional characterization of PCCA mutations causing propionic acidemia. Clavero, S., Martínez, M.A., Pérez, B., Pérez-Cerdá, C., Ugarte, M., Desviat, L.R. Biochim. Biophys. Acta (2002) [Pubmed]
  9. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Pérez, B., Desviat, L.R., Rodríguez-Pombo, P., Clavero, S., Navarrete, R., Perez-Cerdá, C., Ugarte, M. Mol. Genet. Metab. (2003) [Pubmed]
  10. Assignment of the human gene propionyl coenzyme A carboxylase, alpha-chain, (PCCA) to chromosome 13q32 by in situ hybridization. Kennerknecht, I., Klett, C., Hameister, H. Genomics (1992) [Pubmed]
  11. Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase. Rodríguez-Pombo, P., Pérez-Cerdá, C., Pérez, B., Desviat, L.R., Sánchez-Pulido, L., Ugarte, M. Biochim. Biophys. Acta (2005) [Pubmed]
  12. An alternating sheared AA pair and elements of stability for a single sheared purine-purine pair flanked by sheared GA pairs in RNA. Chen, G., Kennedy, S.D., Qiao, J., Krugh, T.R., Turner, D.H. Biochemistry (2006) [Pubmed]
  13. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Ugarte, M., Pérez-Cerdá, C., Rodríguez-Pombo, P., Desviat, L.R., Pérez, B., Richard, E., Muro, S., Campeau, E., Ohura, T., Gravel, R.A. Hum. Mutat. (1999) [Pubmed]
  14. Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes. Clavero, S., Pérez, B., Rincón, A., Ugarte, M., Desviat, L.R. Hum. Genet. (2004) [Pubmed]
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