Alternative titles; symbols
HGNC Approved Gene Symbol: PSAT1
SNOMEDCT: 718603002;
Cytogenetic location: 9q21.2 Genomic coordinates (GRCh38) : 9:78,297,125-78,330,093 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.2 | Neu-Laxova syndrome 2 | 616038 | Autosomal recessive | 3 |
| Phosphoserine aminotransferase deficiency | 610992 | Autosomal recessive | 3 |
L-serine serves as a building block for protein synthesis and can be modified in different metabolic pathways to generate several essential compounds. Although it is available from dietary sources, L-serine can be synthesized from 3-phosphoglycerate via 3 enzymatic steps in the phosphorylated pathway. PSAT (EC 2.6.1.52) catalyzes the second step in the pathway, conversion of 3-phosphohydroxypyruvate into 3-phosphoserine (Baek et al., 2003).
Baek et al. (2003) cloned 2 PSAT1 splice variants, which they called PSAT-alpha and -beta, from a human Jurkat T-cell cDNA library. The full-length PSAT-beta transcript encodes a deduced 370-amino acid protein with a calculated molecular mass of 40 kD. PSAT-alpha lacks exon 8 and encodes a deduced 324-amino acid protein with a calculated molecular mass of 35.2 kD. Compared with PSAT-beta, PSAT-alpha lacks 46 amino acids. Both proteins contain a conserved binding domain for the cofactor pyridoxal 5-prime-phosphate (vitamin B6). PSAT-beta shares 92.4% amino acid similarity with its mouse homolog. PSAT-beta orthologs were present in all species examined, including plants, insects, and bacteria. Northern blot analysis detected highest expression of a 2.2-kb transcript in brain, liver, kidney, and pancreas, with weaker expression in thymus, prostate, testis, and colon. No expression was detected in spleen, ovary, small intestine, peripheral blood mononuclear cells, heart, placenta, lung, and skeletal muscle. RT-PCR detected both variants in all human cell lines examined, and PSAT-beta was always the more abundant form. Western blot analysis detected the 40-kD PSAT-beta protein in all human cell lines examined, whereas the 32.5-kD PSAT-alpha protein was only weakly expressed in hepatoma and chronic myelogenous leukemia cell lines. The level of PSAT-beta protein was proportional to the amount of PSAT-beta mRNA detected in these cell lines.
Baek et al. (2003) determined that the PSAT gene contains 9 exons and spans 56 kb.
By genomic sequence analysis, Baek et al. (2003) mapped the PSAT1 gene to chromosome 9q21.31.
Using Northern blot analysis, Misrahi et al. (1987) showed that Psat, which they called Epip, was upregulated in a dose-dependent manner by progesterone and more weakly by estradiol in rabbit endometrium. Progesterone and estradiol inhibitors decreased the elicited Psat expression. PSAT mRNA was detected in human endometrium during the luteal phase, but not during the follicular phase or during pregnancy.
Baek et al. (2003) found that enzymatic activity of recombinant PSAT-beta was nearly 7 times higher than that of PSAT-alpha, which showed barely detectable activity. Both PSAT-alpha and -beta could rescue deletion of their S. cerevisiae counterpart. Northern blot analysis of synchronized Jurkat T cells showed that expression of PSAT reached a maximum in S phase and decreased to basal levels as cells moved to the G2/M boundary.
Phosphoserine Aminotransferase Deficiency
Hart et al. (2007) identified PSAT deficiency (PSATD; 610992) in a brother and sister who showed low concentrations of serine and glycine in plasma and cerebrospinal fluid. The index patient presented with intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation and died at age 7 months despite supplementation with serine and glycine from age 11 weeks. His sister received treatment from birth, which led to a normal outcome at age 3 years. Measurement of PSAT1 activity in cultured fibroblasts in the index patient was inconclusive, but mutational analysis revealed compound heterozygosity for mutations in the PSAT1 gene in both sibs: a frameshift mutation (G107del; 610936.0001) and a missense mutation (D100A; 610936.0002).
In a 7-month-old female with PSAT deficiency, Glinton et al. (2018) identified compound heterozygous mutations in the PSAT1 gene (c.432delA, 610936.0006 and A15V, 610936.0007). Plasma amino acids showed low serine and low/normal glycine, and CSF amino acids showed low serine and normal glycine. Analysis of the newborn screening blood spot of this patient showed low serine with a Z-score of -2.4. Metabolomic analysis in plasma showed low glycerophospholipids including low phosphatidylcholine, suggesting that PSAT may play a role in CNS development.
Debs et al. (2021) identified compound heterozygous mutations in the PSAT1 gene (T156M, 610036.0008 and A15P, 610036.0009) in a woman with PSATD. The mutations were identified by whole-exome sequencing.
In a Turkish boy (patient 2), born to consanguineous parents, with PSATD, Brassier et al. (2016) identified homozygosity for a S43R mutation (610036.0010) in the PSAT1 gene. Purified PSAT1 with the S43R mutation had a decreased Vmax and increased Km compared to wildtype protein.
Neu-Laxova Syndrome 2
In affected patients from 6 unrelated families with Neu-Laxova syndrome-2 (NLS2; 616038), Acuna-Hidalgo et al. (2014) identified homozygous or compound heterozygous mutations in the PSAT1 gene (610936.0003-610936.0005). The mutations, which were found by homozygosity mapping combined with detailed exome sequencing, were confirmed by Sanger sequencing. The mutations segregated with the disorder in all families with available material; functional studies were not performed. Acuna-Hidalgo et al. (2014) noted that some features of the phenotype overlapped with, but were more severe than, those reported by Hart et al. (2007) in patients with PSAT deficiency, suggesting that the prenatal lethality of NLS2 represents the more severe end of a phenotypic spectrum. The findings emphasized the critical importance of serine availability in early embryonic and fetal development.
In 2 sibs with phosphoserine aminotransferase deficiency (PSATD; 610992), Hart et al. (2007) detected compound heterozygosity for mutations in the PSAT1 gene. The paternal allele carried a frameshift mutation (c.107delG) in exon 2. The maternal allele carried a c.299A-C transversion in exon 4, resulting in an asp100-to-ala (D100A) substitution (610936.0002).
For discussion of the asp100-to-ala (D100A) mutation in the PSAT1 gene that was found in compound heterozygous state in 2 sibs with PSAT deficiency (PSATD; 610992) by Hart et al. (2007), see 610936.0001.
In a fetus, the offspring of consanguineous parents, with Neu-Laxova syndrome-2 (NLS2; 616038), Acuna-Hidalgo et al. (2014) identified a homozygous complex insertion/deletion mutation in the last exon of the PSAT1 gene (c.1023_1027delinsAGACCT), resulting in a frameshift and premature termination (Arg342AspfsTer6). The mutation was found by detailed reanalysis of exome sequencing data from the patient; the variant was not correctly identified by initial exome sequencing. DNA from a similarly affected sib and from the unaffected parents was not available for segregation analysis. Functional studies of the variant were not performed, but skin biopsy obtained from the fetus showed normal mRNA levels, suggesting that the mutation does not lead to an unstable RNA.
In 2 affected stillborn fetuses and an affected preterm newborn who died within the first week of life with Neu-Laxova syndrome-2 (NLS2; 616038), all from different families, Acuna-Hidalgo et al. (2014) identified a homozygous c.296C-T transition in the PSAT1 gene, resulting in an ala99-to-val (A99V) substitution at a highly conserved residue. The mutation was found by detailed reanalysis of exome sequencing data from the first patient; it was not correctly identified by initial exome sequencing because of its proximity to a known SNP. An affected newborn from a fourth family was found to be compound heterozygous for A99V and S179L (610936.0005). All 4 families originated from the Middle East and had either Iranian or Turkish ancestry, suggesting a founder effect that was confirmed by haplotype analysis in 2 Turkish families. The mutation was not found in the Exome Variant Server database; functional studies of the variant were not performed.
In the unaffected parents and an unaffected sib of a fetus with Neu-Laxova syndrome-2 (NLS2; 616038), Acuna-Hidalgo et al. (2014) identified a heterozygous c.536C-T transition in the PSAT1 gene, resulting in a ser179-to-leu (S179L) substitution at a highly conserved residue close to the cofactor binding site. The parents were related, suggesting that the affected fetus was homozygous for the mutation, but only low-quality DNA extracted from formalin-fixed paraffin-embedded material was available from the fetus. The S179L mutation was found in compound heterozygosity with another pathogenic PSAT1 mutation (A99V; 610936.0004) in a hypotrophic newborn who died at age 10 days. The S179L mutation was not found in the Exome Variant Server database; functional studies of the variant were not performed.
By whole-exome sequencing in a patient with infantile phosphoserine aminotransferase deficiency (PSATD; 610992), Glinton et al. (2018) identified compound heterozygous mutations in the PSAT1 gene: a 1-bp deletion (c.432delA), predicting a frameshift and a premature termination codon (Glu145MetfsTer49), and a c.44C-T transition, resulting in an ala15-to-val (A15V; 610036.0007) substitution.
For discussion of the c.44C-T transition in the PSAT1 gene, resulting in an ala15-to-val (A15V) substitution, that was found in compound heterozygous state in a patient with infantile PSAT deficiency (PSATD; 610992) by Glinton et al. (2018), see 610936.0006.
In a woman with phosphoserine aminotransferase deficiency (PSATD; 610992), Debs et al. (2021) identified compound heterozygous mutations in the PSAT1 gene: a c.467C-T transition (c.467C-T, NM_058179.2), resulting in a thr156-to-met (T156M) substitution, and a c.43G-C transversion, resulting in an ala15-to-pro (A15P; 610036.0009) substitution. The mutations were identified by whole-exome sequencing. The A15P mutation was present in the gnomAD database (v2.1.1) at an allele frequency of 12/258286, and the T156M mutation was present in the gnomAD database (v2.1.1) at an allele frequency of 24/282878.
For discussion of the c.43G-C transversion (c.43G-C, NM_058179.2) in the PSAT1 gene, resulting in an ala15-to-pro (A15P) substitution, that was identified in compound heterozygous state in a patient with phosphoserine aminotransferase deficiency (PSATD; 610992) by Debs et al. (2021), see 610036.0008.
In a Turkish boy (patient 2), born to consanguineous parents, with phosphoserine aminotransferase deficiency (PSATD; 610992), Brassier et al. (2016) identified homozygosity for a c.129T-G transversion in the PSAT1 gene, resulting in a ser43-to-arg (S43R) substitution at a conserved residue. The mutation was identified by microsatellite homozygosity mapping and the parents were mutation carriers. Purified PSAT1 with the S43R mutation had a decreased Vmax and increased Km compared to wildtype protein. The patient had very low levels of serine in the plasma and cerebrospinal fluid.
Acuna-Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M. H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., and 18 others. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am. J. Hum. Genet. 95: 285-293, 2014. [PubMed: 25152457] [Full Text: https://doi.org/10.1016/j.ajhg.2014.07.012]
Baek, J. Y., Jun, D. Y., Taub, D., Kim, Y. H. Characterization of human phosphoserine aminotransferase involved in the phosphorylated pathway of L-serine biosynthesis. Biochem. J. 373: 191-200, 2003. [PubMed: 12633500] [Full Text: https://doi.org/10.1042/BJ20030144]
Brassier, A., Valayannopoulos, V., Bahi-Buisson, N., Wiame, E., Hubert, L., Boddaert, N., Kaminska, A., Habarou, F., Desguerre, I., Van Schaftingen, E., Ottolenghi, C., de Lonlay, P. Two new cases of serine deficiency disorders treated with l-serine. Europ. J. Paediat. Neurol. 20: 53-60, 2016. [PubMed: 26610677] [Full Text: https://doi.org/10.1016/j.ejpn.2015.10.007]
Debs, S., Ferreira, C. R., Groden, C., Kim, H. J., King, K. A., King, M. C., Lehky, T., Cowen, E. W., Brown, L. H., Merideth, M., Owen, C. M., Macnamara, E., Toro, C., Gahl, W. A., Soldatos, A. Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy. Am. J. Med. Genet. 185A: 2102-2107, 2021. [PubMed: 34089226] [Full Text: https://doi.org/10.1002/ajmg.a.62245]
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, 2018. [PubMed: 29269105] [Full Text: https://doi.org/10.1016/j.ymgme.2017.12.009]
Hart, C. E., Race, V., Achouri, Y., Wiame, E., Sharrard, M., Olpin, S. E., Watkinson, J., Bonham, J. R., Jaeken, J., Matthijs, G., Van Schaftingen, E. Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am. J. Hum. Genet. 80: 931-937, 2007. [PubMed: 17436247] [Full Text: https://doi.org/10.1086/517888]
Misrahi, M., Atger, M., Milgrom, E. A novel progesterone-induced messenger RNA in rabbit and human endometria: cloning and sequence analysis of the complementary cDNA. Biochemistry 26: 3975-3982, 1987. [PubMed: 3651428] [Full Text: https://doi.org/10.1021/bi00387a035]