Alternative titles; symbols
HGNC Approved Gene Symbol: PSPH
SNOMEDCT: 124432005;
Cytogenetic location: 7p11.2 Genomic coordinates (GRCh38): 7:56,011,064-56,051,444 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p11.2 | Phosphoserine phosphatase deficiency | 614023 | Autosomal recessive | 3 |
The PSPH gene encodes phosphoserine phosphatase (EC 3.1.3.3), which catalyzes the final and irreversible step of L-serine synthesis (summary by Vincent et al., 2015).
By starch gel electrophoresis, Moro-Furlani et al. (1980) detected multiple isozymes of PSP in a wide range of tissues. They suggested that rare electrophoretic variants were probably due to allelic variation at the structural locus, and that common variation existed due to secondary modification. The 3-banded isozyme pattern seen in heterozygotes (PSP2-1 and PSP3-1) suggested that PSP is dimeric.
Collet et al. (1997) cloned the human PSP cDNA, which encodes a 225-amino acid polypeptide. The cDNA was expressed and yielded a 25-kD protein with the expected phosphatase activity.
By study of somatic cell hybrids, Koch et al. (1983) assigned the structural gene for PSPH to chromosome 7 in the region pter-q22. By study of patients with structural abnormalities of 7p, Novelli and Dallapiccola (1988) refined the assignment of PSPH to 7p15.2-p15.1. The activity of PSP was increased in a patient with an unbalanced translocation associated with trisomy of the segment 7pter-p15 (Caiulo et al., 1989).
Jaeken et al. (1997) noted that the assignments of the PSPH gene to 7p by Koch et al. (1983) and Novelli and Dallapiccola (1988) were based on gene dosage analysis. By genomic sequence analysis, Veiga-da-Cunha et al. (2004) found that the PSPH gene is located on 7p11.
Phosphoserine Phosphatase Deficiency
In a patient with phosphoserine phosphatase deficiency (PSPHD; 614023), who also had Williams-Beuren syndrome (WBS; 194050) and was originally reported by Jaeken et al. (1997), Veiga-da-Cunha et al. (2004) identified compound heterozygosity for 2 mutations in the PSPH gene (172480.0001; 172480.0002). They noted that the PSPH gene is separated from the elastin gene (ELN; 130160), one of several genes implicated in WBS, by 16.5 Mb. The authors concluded that there was no link between the 2 disorders in this patient.
In affected members of a consanguineous Pakistani family with PSPHD, Vincent et al. (2015) identified a homozygous missense mutation in the PSPH gene (A35T; 172480.0004). The mutation, which was found by homozygosity mapping and Sanger sequencing of candidate genes, segregated with the disorder in the family. Enzymatic analysis showed that the mutant protein had approximately 10-fold lower activity than wildtype.
Associations Pending Confirmation
See 172480.0003 for discussion of a possible association between variation in the PSPH gene and Neu-Laxova syndrome (see 256520).
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 PSPH is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with phosphoserine phosphatase deficiency (PSPHD; 614023) originally reported by Jaeken et al. (1997), Veiga-da-Cunha et al. (2004) identified compound heterozygosity for 2 mutations in the PSPH gene: a 94G-A transition resulting in an asp32-to-asn (D32N) substitution, and a 155T-C transition resulting in a met52-to-thr (M52T; 172480.0002) substitution. The D32N change occurs in a fairly well-conserved region of the protein, and the M52T change in an extremely well-conserved area. The patient's father and mother were heterozygous for the D32N and the M52T mutation, respectively, indicating autosomal recessive inheritance. In vitro expression studies showed that the D32N mutation reduced enzyme activity by 50%, and the M52T mutation virtually abolished enzyme activity. The changes were consistent with kinetic properties observed in the patient's fibroblasts.
For discussion of the met52-to-thr (M52T) mutation in the PSPH gene that was found in compound heterozygous state in a patient with phosphoserine phosphatase deficiency (PSPHD; 614023) by Veiga-da-Cunha et al. (2004), see 172480.0001.
This variant is classified as a variant of unknown significance because its contribution to Neu-Laxova syndrome (see 256520) has not been confirmed.
In the unaffected related parents and an unaffected sib of a fetus with Neu-Laxova syndrome (see 256520), Acuna-Hidalgo et al. (2014) identified a heterozygous 1-bp deletion (c.267delC) in the PSPH gene resulting in a frameshift and premature termination (Gly90AlsfsTer2) predicted to result in complete loss of function. The authors inferred from this that the fetus was homozygous for the mutation; no DNA was available from the fetus to test for homozygosity. The mutation was not present in the Exome Sequencing Project database; functional studies of the variant were not performed. The fetus had multiple congenital anomalies, including intrauterine growth retardation, microcephaly, low-set ears, flat nose, micrognathia, abnormal mouth, digital and limb deformities, rocker-bottom feet, ichthyosis, and widely spaced nipples. Acuna-Hidalgo et al. (2014) noted that some features of the phenotype overlapped with, but were more severe than, those reported in PSPH 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 affected members of a large consanguineous Pakistani family with phosphoserine phosphatase deficiency (PSPHD; 614023), Vincent et al. (2015) identified a homozygous c.103G-A transition (c.103G-A, NM_004577.3) in the PSPH gene, resulting in an ala35-to-thr (A35T) substitution at a highly conserved residue in a small hydrophobic pocket near the catalytic site. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family, and was not present in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases, or in 250 Pakistani controls. Enzymatic analysis showed that the mutant protein had approximately 10-fold lower activity than wildtype, and plasma levels of serine and glycine were decreased in 2 patients tested.
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]
Caiulo, A., Bardoni, B., Camerino, G., Guioli, S., Minelli, A., Piantanida, M., Crosato, F., Dalla Fior, T., Maraschio, P. Cytogenetic and molecular analysis of an unbalanced translocation (X;7)(q28;p15) in a dysmorphic girl. Hum. Genet. 84: 51-54, 1989. [PubMed: 2558067] [Full Text: https://doi.org/10.1007/BF00210670]
Collet, J.-F., Gerin, I., Rider, M. H., Veiga-da-Cunha, M., Van Shaftingen, E. Human L-3-phosphoserine phosphatase: sequence, expression and evidence for a phosphoenzyme intermediate. FEBS Lett. 408: 281-284, 1997. [PubMed: 9188776] [Full Text: https://doi.org/10.1016/s0014-5793(97)00438-9]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Jaeken, J., Detheux, M., Fryns, J.-P., Collet, J.-F., Alliet, P., Van Schaftingen, E. Phosphoserine phosphatase deficiency in a patient with Williams syndrome. J. Med. Genet. 34: 594-596, 1997. [PubMed: 9222972] [Full Text: https://doi.org/10.1136/jmg.34.7.594]
Koch, G. A., Eddy, R. L., Haley, L. L., Byers, M. G., McAvoy, M., Shows, T. B. Assignment of the human phosphoserine gene (PSP) to the pter-q22 region of chromosome 7. Cytogenet. Cell Genet. 35: 67-69, 1983. [PubMed: 6297854] [Full Text: https://doi.org/10.1159/000131839]
Moro-Furlani, A. M., Turner, V. S., Hopkinson, D. A. Genetical and biochemical studies on human phosphoserine phosphatase. Ann. Hum. Genet. 43: 323-333, 1980. [PubMed: 6249179] [Full Text: https://doi.org/10.1111/j.1469-1809.1980.tb01566.x]
Novelli, G., Dallapiccola, B. Gene dosage studies regionally assign the phosphoserine phosphatase gene to 7p15.1 or 2. Ann. Genet. 31: 195-196, 1988. [PubMed: 2851960]
Sparkes, R. S., Mohandas, T., Sparkes, M. C. The human phosphoserine phosphatase gene (PSP) is mapped to chromosome 7 by somatic cell genetic analysis. Cytogenet. Cell Genet. 35: 70-71, 1983. [PubMed: 6297855] [Full Text: https://doi.org/10.1159/000131840]
Veiga-da-Cunha, M., Collet, J.-F., Prieur, B., Jaeken, J., Peeraer, Y., Rabbijns, A., van Schaftingen, E. Mutations responsible for 3-phosphoserine phosphatase deficiency. Europ. J. Hum. Genet. 12: 163-166, 2004. [PubMed: 14673469] [Full Text: https://doi.org/10.1038/sj.ejhg.5201083]
Vincent, J. B., Jamil, T., Rafiq, M. A., Anwar, Z., Ayaz, M., Hameed, A., Nasr, T., Naeem, F., Khattak, N. A., Carter, M., Ahmed, I., John, P., Wiame, E., Andrade, D. M., Schaftingen, E. V., Mir, A., Ayub, M. Phosphoserine phosphatase (PSPH) gene mutation in an intellectual disability family from Pakistan. (Letter) Clin. Genet. 87: 296-298, 2015. [PubMed: 25080166] [Full Text: https://doi.org/10.1111/cge.12445]