Alternative titles; symbols
HGNC Approved Gene Symbol: PHGDH
Cytogenetic location: 1p12 Genomic coordinates (GRCh38): 1:119,711,934-119,744,215 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p12 | Neu-Laxova syndrome 1 | 256520 | Autosomal recessive | 3 |
| Phosphoglycerate dehydrogenase deficiency | 601815 | Autosomal recessive | 3 |
3-Phosphoglycerate dehydrogenase (PHGDH; EC 1.1.1.95) catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the first and rate-limiting step in the phosphorylated pathway of serine biosynthesis, using NAD+/NADH as a cofactor (summary by Cho et al., 2000).
Cho et al. (2000) cloned a cDNA encoding phosphoglycerate dehydrogenase from a human Jurkat T-cell cDNA library. The deduced 533-amino acid protein, with a molecular mass of 56.8 kD, shares 94% sequence identity with rat liver 3-PGDH. Northern blot analysis detected a major 2.1-kb transcript at high levels in prostate, testis, ovary, brain, liver, kidney, and pancreas and at low levels in thymus, colon, and heart. A 710-bp transcript appeared as a weaker band in most tissues in which the 2.1-kb mRNA was expressed, was more significant than the 2.1-kb mRNA in heart, and was the only transcript present in skeletal muscle. The 2.1-kb transcript was also detected in most continuously growing tumor cells tested.
Cho et al. (2000) found that TPA-induced monocytic differentiation of U937 cells, which also resulted in growth arrest, abruptly downregulated the expression of PHGDH. Removal of TPA restored cell growth through the retrodifferentiation process and subsequent expression of PHGDH. These findings suggested that the expression of PHGDH may be regulated at the transcriptional level depending on tissue specificity and cellular proliferative status.
Possemato et al. (2011) developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, they screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, PHGDH is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of estrogen receptor-negative breast cancers. PHGDH catalyzes the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, caused a strong decrease in cell proliferation and a reduction in serine synthesis. Possemato et al. (2011) found that PHGDH suppression does not affect intracellular serine levels, but causes a drop in levels of alpha-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. Possemato et al. (2011) concluded that certain breast cancers are dependent on increased serine pathway flux caused by PHGDH overexpression.
Locasale et al. (2011) found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through PHGDH. An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal number copy gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Locasale et al. (2011) concluded that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
Using 2 radiation hybrid panels, Klomp et al. (2000) mapped the PHGDH gene to chromosome 1q12. However, by fluorescence in situ hybridization, Baek et al. (2000) mapped the PHGDH gene to 1p12.
Phosphoglycerate Dehydrogenase Deficiency
To investigate the molecular basis of phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), Klomp et al. (2000) characterized the PHGDH mRNA sequence and analyzed it for variations in 6 patients from 4 families with this disorder. Five patients in 3 different families were homozygous for a val490-to-met (V490M; 606879.0001) mutation and the sixth patient was homozygous for a val425-to-met (V425M; 606879.0002) mutation. Both mutations were located in the C terminus of the PHGDH gene. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurologic impairment in these patients, the data suggested an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.
Tabatabaie et al. (2009) identified 1 frameshift and 4 missense mutations in the PHGDH gene in 5 patients with phosphoglycerate dehydrogenase deficiency (see, e.g., 606879.0003-606879.0006). Studies in patient fibroblasts showed significant, but incomplete, reduction with missense mutations, including the previously identified V490M and V425M substitutions. Transient overexpression studies in HEK293 cells and molecular modeling onto the partial crystal structure of 3-PGDH suggested that missense mutations associated with 3-PGDH deficiency either primarily affect substrate binding or result in very low residual enzymatic activity.
In a 2-month-old male infant, born to parents who came from the same area in the United Arab Emirates, with PHGDH deficiency, El-Hattab et al. (2016) identified a homozygous missense mutation in the PHGDH gene (G429V; 606879.0011).
In 5 individuals with PHGDHD from 2 unrelated families, Benke et al. (2017) identified homozygous or compound heterozygous mutations in the PHGDH gene (606879.0005 and 606879.0012). Studies in patient fibroblasts showed decreased PHGDH enzyme activity compared to control. Serine and glycine were low in patient plasma and CSF. By metabolomic analysis in plasma from these sisters and the boy previously reported by El-Hattab et al. (2016), Glinton et al. (2017) found low glycerophospholipids including low phosphatidylcholine, suggesting that PHGDH may play a role in CNS development.
In 2 sibs, born to consanguineous parents from China, with PHGDHD, Fu et al. (2023) identified homozygosity for a missense mutation (V404D; 606879.0014) in the regulatory domain of phosphoglycerate dehydrogenase. The authors reviewed the literature on pathogenic variants in the PHGDH gene; they noted 17 variants, mostly in the regulatory domain, associated with PHGDHD, and 13 variants, mostly located in the nucleotide-binding domain, associated with Neu-Laxova syndrome-1 (NLS1; 256520).
In a patient with PHGDHD, Brassier et al. (2016) identified compound heterozygous mutations in the PHGDH gene (R135W, 606879.0004 and R163W, 606879.0015). The mutations were identified by sequencing of a 3-gene panel of genes associated with serine deficiency.
Neu-Laxova Syndrome 1
In 3 patients from unrelated consanguineous Saudi families with Neu-Laxova syndrome-1 (NLS1; 256520), Shaheen et al. (2014) identified 2 different homozygous missense mutations in the PHGDH gene (G140R; 606879.0007 and R163Q; 606879.0008). The mutations were found by a combination of autozygosity mapping and exome sequencing. Both substitutions occurred at highly conserved residues within the NAD(P)-binding domain at the PHGDH dimer interface, suggesting that they would severely interfere with enzyme function. In vitro studies of the variants were not performed. In addition to manifesting classic features of the disorder, 1 of the patients had a dried blood spot that showed low concentrations of serine and glycine, consistent with a biochemical diagnosis of PHGDH deficiency. Shaheen et al. (2014) suggested that the severe phenotype observed in these patients reflects the extreme end of the inborn error of serine metabolism.
Acuna-Hidalgo et al. (2014) identified biallelic mutations in the PHGDH gene (see, e.g., 606879.0009 and 606879.0010) in affected individuals from 3 unrelated families with NLS1. Functional studies of the variants were not performed.
In 3 fetuses with NLS1, conceived by Chinese parents, Bourque et al. (2019) identified homozygosity for a mutation in the PHGDH gene resulting in loss of the translation start codon (M1?; 606879.0013). The start methionine of the PHGDH gene is highly conserved among species, and only 1 transcript had been observed. Although the parents were not known to be related, homozygosity mapping identified an 11.2-Mb region on chromosome 1 shared by the 2 fetuses for which exome sequencing was performed, suggesting that the parents likely shared a distant common ancestor.
In 5 patients from 3 different families (2 Turkish and 1 European), Klomp et al. (2000) found that PHGDH deficiency (PHGDHD; 601815) was related to a homozygous 1468G-A transition predicted to cause a val490-to-met amino acid substitution in the protein.
In a girl, born of a consanguineous Moroccan couple, who was reported by Pineda et al. (2000) to have phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815) and West syndrome, Klomp et al. (2000) found a homozygous 1273G-A transition in the PHGDH gene, resulting in a val425-to-met substitution.
In a Dutch boy with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), Tabatabaie et al. (2009) identified compound heterozygosity for a 1-bp deletion (712delG) in exon 7 and a 403C-T transition in exon 4 of the PHGDH gene, the former causing a frameshift and premature termination codon and the latter resulting in an arg135-to-trp (R135W; 606879.0004) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a markedly decreased V(max). Transfection studies in HEK293 cells with the deletion mutant resulted in undetectable expression of 3-PGDH protein, whereas overexpression of the R135W mutant resulted in a moderate decrease of V(max) without affecting K(m). Molecular modeling of the R135W mutation onto the partial crystal structure of 3-PGDH predicted that the mutation would affect substrate and cofactor binding.
For discussion of the arg135-to-trp (R135W) mutation in the PHGDH gene that was found in compound heterozygous state in a patient with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815) by Tabatabaie et al. (2009), see 606879.0003.
In a patient (patient 1) with PHGDHD, Brassier et al. (2016) identified compound heterozygous mutations in the PHGDH gene: the R135W mutations, which they said resulted from a c.403C-G transition, and a c.487C-T transition, resulting in an arg163-to-trp (R163W; 606879.0015) substitution. The mutations were identified by sequencing of a panel of 3 genes associated with serine deficiency; the mother was found to be a mutation carrier but the father was not available for testing. The patient had very low plasma and CSF serine.
In a Dutch brother and sister with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), born of consanguineous parents, Tabatabaie et al. (2009) identified homozygosity for a 1129G-A transition in exon 10 of the PHGDH gene, resulting in a gly377-to-ser (G377S) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a markedly decreased V(max); transfection studies in HEK293 cells with overexpression of the G377S mutant resulted in a moderate decrease of V(max) without affecting K(m).
In 3 sisters (family 3) with PHGDHD, Benke et al. (2017) identified homozygosity for the c.1129G-A transition (c.1129G-A, NM_006623.3) in the PHGDH gene, resulting in a gly377-to-ser (G377S) substitution. In 2 sisters in an unrelated family (family 1) with PHGDHD, Benke et al. (2017) identified compound heterozygous mutations in the PHGDH gene: G377S and a 1-bp duplication (c.138+2dupT; 606879.0012). Serine and glycine were low in plasma and CSF in the patients from both families.
In a Turkish boy with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), Tabatabaie et al. (2009) identified homozygosity for a 781G-A transition in exon 7 of the PHGDH gene, resulting in a val261-to-met (V261M) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a significant but incomplete reduction in V(max), whereas transfection studies in HEK293 cells with overexpression of the V261M mutant displayed a 4-fold increase in K(m). Molecular modeling of the V261M mutation onto the partial crystal structure of 3-PGDH predicted that the mutation would affect substrate and cofactor binding.
In 2 unrelated patients, each born of consanguineous Saudi parents, with Neu-Laxova syndrome-1 (NLS1; 256520), Shaheen et al. (2014) identified a homozygous c.418G-A transition in the PHGDH gene, resulting in a gly140-to-arg (G140R) substitution at a highly conserved residue within the NAD(P)-binding domain and at the PHGDH dimer interface. The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases, or in 450 Saudi exomes. All 4 unaffected parents were heterozygous for the mutation. Functional studies of the variant were not performed. One of the affected infants died immediately after birth, and the other was stillborn at age 29 weeks.
In a male infant, born of consanguineous Saudi parents, with Neu-Laxova syndrome-1 (NLS1; 256520), Shaheen et al. (2014) identified a homozygous c.488G-A transition in the PHGDH gene, resulting in an arg163-to-gln (R163Q) substitution at a highly conserved residue within the NAD(P)-binding domain, specifically at the PHGDH dimer interface. The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases, or in 450 Saudi exomes. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed.
In a fetus, conceived by consanguineous parents, with Neu-Laxova syndrome-1 (NLS1; 256520), Acuna-Hidalgo et al. (2014) identified a homozygous c.793G-A transition in the PHGDH gene, resulting in a glu265-to-lys (E265K) substitution at a highly conserved residue in close proximity to the substrate binding domain. The mutation, which segregated with the disorder in the family, was not found in the Exome Variant Server database; functional studies were not performed.
In a fetus, conceived by consanguineous parents, with Neu-Laxova syndrome-1 (NLS1; 256520), Acuna-Hidalgo et al. (2014) identified a homozygous c.856G-C transversion in the PHGDH gene, resulting in an ala286-to-pro (A286P) substitution at a highly conserved residue in close proximity to the substrate binding domain. The mutation, which segregated with the disorder in the family, was not found in the Exome Variant Server database; functional studies were not performed.
In a 2-month-old male infant, born to parents who came from the same area in the United Arab Emirates, with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), El-Hattab et al. (2016) identified a homozygous c.1286G-T transversion in the PHGDH gene, resulting in a gly429-to-val (G429V) substitution.
For discussion of the 1-bp duplication (c.138+2dupT, NM_006623.3) in the PHGDH gene that was found in compound heterozygous state in 2 sisters (family 1) with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815) by Benke et al. (2017), see 606879.0005.
By exome sequencing in 3 fetuses, conceived by Chinese parents, with Neu-Laxova syndrome (NLS1; 256520), Bourque et al. (2019) identified a homozygous c.1A-C transversion (c.1A-C, NM_006623.3) in the PHGDH gene, resulting in loss of the translation start codon (Met1?). The start methionine of the PHGDH gene is highly conserved among species, and only 1 transcript has been observed. The variant was not present in the gnomAD database. The variant was classified as likely pathogenic by ACMG criteria. Although the parents were not known to be related, homozygosity mapping identified an 11.2-Mb region on chromosome 1 shared by the 2 fetuses for which exome sequencing was performed, suggesting that the parents likely shared a distant common ancestor.
By exome sequencing in 2 sibs, born to consanguineous parents from China, with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), Fu et al. (2023) identified homozygosity for a c.1211T-A transversion (c.1211T-A, NM_006623.4) in exon 11 of the PHGDH gene, resulting in a val404-to-asp (V404D) substitution in the regulatory domain. Both parents were heterozygous for the variant, which was confirmed by Sanger sequencing. The variant was not present in the gnomAD or ExAC databases and was classified as likely pathogenic by ACMG criteria.
For discussion of the c.487C-T transition in the PHGDH gene, resulting in an arg163-to-trp (R163W) substitution, that was identified in compound heterozygous state in a patient (patient 1) with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815) by Brassier et al. (2016), see 606879.0004.
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El-Hattab, A. W., Shaheen, R., Hertecant, J., Galadari, H. I., Albaqawi, B. S., Nabil, A., Alkuraya, F. S. On the phenotypic spectrum of serine biosynthesis. J. Inherit. Metab. Dis. 39: 373-381, 2016. [PubMed: 26960553] [Full Text: https://doi.org/10.1007/s10545-016-9921-5]
Fu, J., Chen, L., Su, T., Xu, S., Liu, Y. Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: case report and literature review. Int. J. Dev. Neurosci. 83: 44-52, 2023. [PubMed: 36308023] [Full Text: https://doi.org/10.1002/jdn.10236]
Glinton, K. E., Benke, P. J., Lines, M. A., Geraghty, M. T., Chakraborty, P., Al-Dirbashi, O. Y., Jiang, Y., Kennedy, A. D., Grotewiel, M. S., Sutton, V. R., Elsea, S. H., El-Hattab, A. W. Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling. Molec. Genet. Metab. 123: 309-316, 2017. [PubMed: 29269105] [Full Text: https://doi.org/10.1016/j.ymgme.2017.12.009]
Klomp, L. W. J., de Koning, T. J., Malingre, H. E. M., van Beurden, E. A. C. M., Brink, M., Opdam, F. L., Duran, M., Jaeken, J., Pineda, M., van Maldergem, L., Poll-The, B. T., van den Berg, I. E. T., Berger, R. Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. Am. J. Hum. Genet. 67: 1389-1399, 2000. [PubMed: 11055895] [Full Text: https://doi.org/10.1086/316886]
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., Sasaki, A. T., Anastasiou, D., and 14 others. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43: 869-874, 2011. [PubMed: 21804546] [Full Text: https://doi.org/10.1038/ng.890]
Pineda, M., Vilaseca, M. A., Artuch, R., Santos, S., Garcia Gonzales, M. M., Sau, I., Aracil, A., Van Schaftingen, E., Jaeken, J. 3-Phosphoglycerate dehydrogenase deficiency in a patient with West syndrome. Dev. Med. Child Neurol. 42: 629-633, 2000. [PubMed: 11034457] [Full Text: https://doi.org/10.1017/s0012162200001171]
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., Chen, W. W., Barrett, F. G., and 15 others. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476: 346-350, 2011. [PubMed: 21760589] [Full Text: https://doi.org/10.1038/nature10350]
Shaheen, R., Rahbeeni, Z., Alhashem, A., Faqeih, E., Zhao, Q., Xiong, Y., Almoisheer, A., Al-Qattan, S. M., Almadani, H. A., Al-Onazi, N., Al-Baqawi, B. S., Saleh, M. A., Alkuraya, F. S. Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. Am. J. Hum. Genet. 94: 898-904, 2014. [PubMed: 24836451] [Full Text: https://doi.org/10.1016/j.ajhg.2014.04.015]
Tabatabaie, L., de Koning, T. J., Geboers, A. J. J. M., van den Berg, I. E. T., Berger, R., Klomp, L. W. J. Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum. Mutat. 30: 749-756, 2009. [PubMed: 19235232] [Full Text: https://doi.org/10.1002/humu.20934]