HGNC Approved Gene Symbol: PC
SNOMEDCT: 87694001; ICD10CM: E74.4;
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:66,848,420-66,958,383 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Pyruvate carboxylase deficiency | 266150 | Autosomal recessive | 3 |
Pyruvate carboxylase (EC 6.4.1.1) is a nuclear-encoded mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. It is a key regulatory enzyme in gluconeogenesis, lipogenesis, and neurotransmitter synthesis. Human PC is a tetramer composed of identical subunits (Barden et al., 1975).
Using an oligonucleotide probe specific for the amino acid sequence at the biotin site of pyruvate carboxylase to screen a human liver cDNA library, Freytag and Collier (1984) isolated 3 cDNA clones for pyruvate carboxylase. Northern blot analysis detected a 4.2-kb mRNA.
Wexler et al. (1994) isolated a PC cDNA, which encodes a deduced 1,178-amino acid protein with a molecular mass of 129.6 kD for the full-length precursor and 127.4 kD for the mature apoprotein. Northern blot analysis demonstrated that the highest level of PC mRNA is in the liver. Based on homology with other biotin-containing proteins, the ATP, pyruvate, and biotin-binding sites were identified. MacKay et al. (1994) isolated and cloned PC cDNA from human kidney.
Carbone et al. (1998) characterized the PC gene by PCR amplification, subcloning, and sequencing.
Carbone et al. (1998) determined that the PC gene contains 19 exons spanning approximately 16 kb of genomic DNA.
Using Southern blotting of human-Chinese hamster somatic cell hybrids, Freytag and Collier (1984) localized the PC gene to the long arm of chromosome 11.
Rochelle et al. (1992) indicated that the corresponding locus in the mouse is located on chromosome 19 near the centromere. Comparative mapping suggested that the human PC locus is in the proximal part of 11q, perhaps 11q12-q13.
Using fluorescence in situ hybridization to normal chromosomes and chromosomes carrying the FRA11A fragile site (see 616109), Walker et al. (1995) mapped PC to 11q13, distal to FRA11A, thus localizing it to 11q13.4-q13.5. Perucca-Lostanlen et al. (1997) used fluorescence in situ hybridization with yeast artificial chromosome and cosmid probes on metaphase chromosomes of patients expressing the fragile site to show that FRA11A is situated centromeric to ACTN3 (102574) and telomeric to D11S913, these markers being within an interval of approximately 1 Mb in the 11q13.3 region.
In 11 Ojibwa and 2 Cree patients with group A pyruvate carboxylase deficiency (266150), Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). In 2 brothers of Micmac origin, they identified a transversion mutation in the PC gene (608786.0002). Carrier frequency was estimated to be as high as 1 in 10 in some groupings. The 2 point mutations were located in the region of homology conserved among yeast, rat, and human PC, in the vicinity of the carboxylation domain of the enzyme.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human PC is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Brun et al. (1999) referred to pyruvate carboxylase as a key enzyme in the gluconeogenesis and anaplerotic metabolic pathways. Anaplerotic is a somewhat archaic term derived from the Greek stems ana, meaning 'for up,' and plerotic, meaning 'for filling.' The adjective anaplerotic refers to a reaction that effects best the formation of an intermediate of the tricarboxylic acid cycle, in order to maintain the intracellular concentration of it, or of another such intermediate, as those intermediates are utilized for biosynthesis.
In 11 Ojibwa and 2 Cree Amerindian patients with simple pyruvate carboxylase deficiency (266150), Carbone et al. (1998) identified a homozygous 1828G-A transition in the PC gene, resulting in an ala610-to-thr (A610T) substitution.
In 2 Micmac brothers from Nova Scotia with simple pyruvate carboxylase deficiency (266150), Carbone et al. (1998) identified a 2229G-T transversion in the PC gene, resulting in a met743-to-ile (M743I) substitution in the carboxylation domain of the enzyme.
In affected members of a consanguineous family with pyruvate carboxylase deficiency (266150), Wexler et al. (1998) identified a homozygous 434T-C transition in the PC gene, resulting in a val145-to-ala (V145A) substitution. Both parents were heterozygous for the mutation. The patients were found to have low PC activity (range 2-25% of control) in blood lymphocytes and skin fibroblasts associated with either diminished or normal protein levels.
In an affected brother and sister from a consanguineous family with pyruvate carboxylase deficiency (266150), Wexler et al. (1998) identified a homozygous 1351C-T transition the PC gene, resulting in an arg451-to-cys (R451C) substitution. Both parents were heterozygous for the mutation. Both mutations occurred in relatively conserved amino acid residues and were located in the biotin carboxylase domain.
In 2 brothers with severe (type B) pyruvate carboxylase deficiency (266150), Carbone et al. (2002) found compound heterozygosity for 2 mutations in the PC gene: a TAGG deletion at the exon 15/intron 15 splice site (IVS15+2-5delTAGG) and a dinucleotide deletion in exon 16 (2491_2492delGT; 608786.0006). By RT-PCR and sequencing of aberrant transcripts, Carbone et al. (2002) found that the splice site mutation resulted in the retention of intron 15 during pre-mRNA splicing. In addition, both deletions were predicted to result in a frameshift to generate a premature termination codon such that the encoded mRNA would be subject to nonsense-mediated decay. In 1 brother, the diagnosis was made at the age of 4 hours and death occurred at 7 weeks; in the younger brother, the diagnosis was made in the fetus and death was in the neonatal period.
For discussion of the dinucleotide deletion in exon 16 (2491_2492delGT) of the PC gene that was found in compound heterozygous state in 2 brothers with severe (type B) pyruvate carboxylase deficiency (266150) by Carbone et al. (2002), see (608786.0005).
In a patient with type A pyruvate carboxylase deficiency (266150), Monnot et al. (2009) identified a homozygous 467G-A transition in exon 3 of the PC gene, resulting in an arg156-to-gln (R156Q) substitution in the biotin carboxylase domain. The mutation had no detectable effect on mRNA size or amount. Monnot et al. (2009) observed that the relatively milder type A phenotype results from missense mutations in the PC gene.
In a patient with type B pyruvate carboxylase deficiency (266150), Monnot et al. (2009) identified compound heterozygosity for 2 mutations in the PC gene: a 1748G-T transversion in exon 12, resulting in an arg583-to-leu (R583L) substitution in the carboxytransferase domain, and a 1-bp duplication in exon 17 (2876dupT; 608786.0009), resulting in a frameshift, nonsense-mediated mRNA decay, and no functional protein. The R583L mutation had no detectable effect on mRNA size or amount. Monnot et al. (2009) commented that patients with the relatively more severe type B tend to have at least 1 truncating mutation in the PC gene.
For discussion of the 1-bp duplication (2876dupT) in exon 17 of the PC gene that was found in a patient with type B pyruvate carboxylase deficiency (266150) by Monnot et al. (2009), see 608786.0008.
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Brun, N., Robitaille, Y., Grignon, A., Robinson, B. H., Mitchell, G. A., Lambert, M. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am. J. Med. Genet. 84: 94-101, 1999. [PubMed: 10323732]
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Monnot, S., Serre, V., Chadefaux-Vekemans, B., Aupetit, J., Romano, S., De Lonlay, P., Rival, J.-M., Munnich, A., Steffann, J., Bonnefont, J.-P. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum. Mutat. 30: 734-740, 2009. [PubMed: 19306334] [Full Text: https://doi.org/10.1002/humu.20908]
Perucca-Lostanlen, D., Hecht, B. K., Courseaux, A., Grosgeorge, J., Hecht, F., Gaudray, P. Mapping FRA11A, a folate-sensitive fragile site in human chromosome band 11q13.3. Cytogenet. Cell Genet. 79: 88-91, 1997. [PubMed: 9533019] [Full Text: https://doi.org/10.1159/000134689]
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Wexler, I. D., Du, Y., Lisgaris, M. V., Mandal, S. K., Freytag, S. O., Yang, B.-S., Liu, T.-C., Kwon, M., Patel, M. S., Kerr, D. S. Primary amino acid sequence and structure of human pyruvate carboxylase. Biochim. Biophys. Acta 1227: 46-52, 1994. [PubMed: 7918683] [Full Text: https://doi.org/10.1016/0925-4439(94)90105-8]
Wexler, I. D., Kerr, D. S., Du, Y., Kaung, M. M., Stephenson, W., Lusk, M. M., Wappner, R. S., Higgins, J. J. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediat. Res. 43: 579-584, 1998. [PubMed: 9585002] [Full Text: https://doi.org/10.1203/00006450-199805000-00004]