Alternative titles; symbols
HGNC Approved Gene Symbol: PDP1
SNOMEDCT: 1003847003;
Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38) : 8:93,916,923-93,926,068 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.1 | Pyruvate dehydrogenase phosphatase deficiency | 608782 | Autosomal recessive | 3 |
Pyruvate dehydrogenase phosphatase (PDP) is a Mg(2+)-dependent and Ca(2+)-stimulated protein serine phosphatase that catalyzes the dephosphorylation and concomitant reactivation of the mitochondrial pyruvate dehydrogenase multienzyme complex (PDHC). Bovine PDP is a heterodimer consisting of a catalytic subunit (PPM2C) with an apparent molecular mass of about 50 kD and a flavoprotein subunit of about 97 kD (Lawson et al., 1993).
Lawson et al. (1993) isolated and assembled a full-length cDNA for bovine PPM2C, which the authors called PDPc. Using purified recombinant bovine PPM2C, they demonstrated that the activity toward the bovine pyruvate dehydrogenase complex was magnesium-dependent and calcium-stimulated. Northern blot analysis detected a PPM2C transcript in bovine heart, brain, and lung.
Huang et al. (1998) cloned rat PPMC2, which they called PDP1. The deduced 538-amino acid protein contains a 71-amino acid N-terminal mitochondrial targeting sequence followed by the catalytic domain. Following cleavage, the 467-amino acid mature protein has a calculated molecular mass of about 52.6 kD. By EST database searching, Huang et al. (1998) found several ESTs corresponding to human PPMC2. Western blot analysis detected predominant expression of PPMC2 in the mitochondrial fraction purified from rat skeletal muscle and much lower expression in mitochondrial fractions purified from rat liver and a mouse adipocyte cell line.
Stumpf (2025) mapped the PDP1 gene to chromosome 8q22.1 based on an alignment of the PDP1 sequence (GenBank AK126862) with the genomic sequence (GRCh38).
Huang et al. (1998) found that both recombinant rat Pdp1 and Pdp2 (615499) showed high specificity for the pyruvate dehydrogenase complex and little to no activity for the related mitochondrial multienzyme complex, branched-chain alpha-ketoacid dehydrogenase (see 608348). However, the phosphatases showed significantly different kinetics and dependence on cofactors. Pdp2 showed almost 10-fold lower sensitivity to Mg(2+) than Pdp1, and only Pdp1 was regulated by Ca(2+). Pdp2 also showed sensitivity to spermine, which had no effect on Pdp1.
Maj et al. (2005) found homozygous mutation of the PDP1 gene (605993.0001) in 2 brothers with pyruvate dehydrogenase phosphatase deficiency (PDHPD; 608782).
In a female infant with lactic acidosis due to pyruvate dehydrogenase phosphatase deficiency, who died during an episode of acute respiratory distress at age 6 months, Cameron et al. (2009) identified homozygosity for a nonsense mutation in the PDP1 gene (605993.0002).
In a 7-year-old Hispanic boy with PDHPD, Bedoyan et al. (2019) identified homozygosity for a 1-bp duplication in the PDP1 gene (605993.0002). Both activated and inactivated pyruvate dehydrogenase complex activities were low in patient fibroblasts and lymphocytes, whereas dihydrolipoamide (E3) activity was normal. Branched-chain 2-ketoacid dehydrogenase (BCKDH) activity was also reduced in patient fibroblasts, leading Bedoyan et al. (2019) to hypothesize that there may be a shared regulatory function for PDP1 in PDHC and BCKDH.
In 2 brothers of Turkish origin, the children of first-cousin parents, with pyruvate dehydrogenase phosphatase deficiency (PDHPD; 608782), Maj et al. (2005) found homozygosity for a 3-bp deletion in the PDP1 gene as the cause of the disorder. The deletion removed the evolutionarily conserved leucine residue from position 213 of the protein. A recombinant version of this protein had a very reduced (less than 5%) ability to activate purified PDHC. Reduced steady-state levels of PDP1 in the patient's fibroblasts coupled with the low catalytic activity of the mutant PDP1 resulted in native PDHC activity being reduced, but this could be corrected by the addition of recombinant wildtype PDP1.
In a female infant with lactic acidosis due to pyruvate dehydrogenase phosphatase deficiency (PDHPD; 608782), born of consanguineous Pakistani parents, Cameron et al. (2009) identified homozygosity for a 277G-T transversion in the PDP1 gene, resulting in a glu93-to-ter (E93X) substitution. The unaffected parents were both heterozygous for the mutation. The patient had only partially reduced native PDHC activity; Western blot analysis of fibroblast mitochondria showed complete absence of PDP1 protein with normal levels of the PDP2 (615499) isoform, suggesting partial compensation by the latter. At 6 months of age, the patient developed acute respiratory distress and died; no autopsy was performed.
In a 7-year-old Hispanic boy with pyruvate dehydrogenase phosphatase deficiency (PDHPD; 608782), Bedoyan et al. (2019) identified homozygosity for a 1-bp duplication (c.575dupT) in the PDP1 gene, predicted to cause a frameshift and a premature termination (Leu192PhefsTer5). The mutation, which was found by next-generation sequencing of a panel of 23 genes associated with pyruvate metabolism, was confirmed by Sanger sequencing. The parents were confirmed to be carriers of the mutation. PDP1 protein expression was absent in patient fibroblasts. Both activated and inactivated pyruvate dehydrogenase complex activities were low in patient fibroblasts and lymphocytes, whereas dihydrolipoamide (E3) activity was normal.
Bedoyan, J. K., Hecht, L., Zhang, S., Tarrant, S., Bergin, A., Demirbas, D., Yang, E., Shin, H. K., Grahame, G. J., DeBrosse, S. D., Hoppel, C. L., Kerr, D. S., Berry, G. T. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 48: 26-35, 2019. [PubMed: 31392110] [Full Text: https://doi.org/10.1002/jmd2.12054]
Cameron, J. M., Maj, M., Levandovskiy, V., Barnett, C. P., Blaser, S., MacKay, N., Raiman, J., Feigenbaum, A., Schulze, A., Robinson, B. H. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum. Genet. 125: 319-326, 2009. [PubMed: 19184109] [Full Text: https://doi.org/10.1007/s00439-009-0629-6]
Huang, B., Gudi, R., Wu, P., Harris, R. A., Hamilton, J., Popov, K. M. Isoenzymes of pyruvate dehydrogenase phosphatase: DNA-derived amino acid sequences, expression, and regulation. J. Biol. Chem. 273: 17680-17688, 1998. [PubMed: 9651365] [Full Text: https://doi.org/10.1074/jbc.273.28.17680]
Lawson, J. E., Niu, X.-D., Browning, K. S., Trong, H. L., Yan, J., Reed, L. J. Molecular cloning and expression of the catalytic subunit of bovine pyruvate dehydrogenase phosphatase and sequence similarity with protein phosphatase 2C. Biochemistry 32: 8987-8993, 1993. [PubMed: 8396421] [Full Text: https://doi.org/10.1021/bi00086a002]
Maj, M. C., MacKay, N., Levandovskiy, V., Addis, J., Baumgartner, E. R., Baumgartner, M. R., Robinson, B. H., Cameron, J. M. Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J. Clin. Endocr. Metab. 90: 4101-4107, 2005. [PubMed: 15855260] [Full Text: https://doi.org/10.1210/jc.2005-0123]
Stumpf, A. M. Personal Communication. Baltimore, Md. 3/06/2025.