Alternative titles; symbols
HGNC Approved Gene Symbol: PTDSS1
SNOMEDCT: 1393001;
Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38): 8:96,261,902-96,336,995 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.1 | Lenz-Majewski hyperostotic dwarfism | 151050 | Autosomal dominant | 3 |
Phosphatidylserine (PS) accounts for 5 to 10% of cell membrane phospholipids. In addition to its role as a structural component, PS is involved in cell signaling, blood coagulation, and apoptosis. PS is synthesized by a calcium-dependent base-exchange reaction catalyzed by PS synthases (EC 2.7.8.8), like PTDSS1, that exchange L-serine for the polar head group of phosphatidylcholine (PC) or phosphatidylethanolamine (PE) (Sturbois-Balcerzak et al., 2001).
By sequencing clones obtained from a size-fractionated cDNA library developed from the human immature myeloid cell line KG-1, Nomura et al. (1994) cloned PTDSS1, which they designated KIAA0024. The deduced 473-amino acid protein has transmembrane domains and a putative tyrosine phosphorylation site, and it shares 97.3% identity with Chinese hamster PS synthase. Northern blot analysis detected PTDSS1 expression in all human tissues and cell lines examined, with highest levels in heart, lung, liver, and kidney.
Using RT-PCR, Sturbois-Balcerzak et al. (2001) detected Pss1 expression in all mouse tissues examined, with highest expression in kidney, liver, brain, heart, lung, and testis.
By database analysis and PCR of a HeLa cell cDNA library, Tomohiro et al. (2009) cloned PTDSS1 and PTDSS2 (612793), which they called PSS1 and PSS2, respectively. SDS-PAGE showed that epitope-tagged PSS1 and PSS2 localized to membrane fractions of transfected HeLa cells.
Sousa et al. (2014) found that PTDSS1 expression was enriched in the brain and skin of human fetuses, with lower levels of expression in bone.
Stone and Vance (2000) found that Pss1 and Pss2 localized exclusively to the mitochondrial-associated membrane (MAM) subcompartment of the endoplasmic reticulum (ER) in rodent cell lines and in mouse liver. Mouse liver MAM used PC and PE as substrates for PS biosynthesis, whereas ER membranes used only PE.
Using in vitro enzyme assays, Sturbois-Balcerzak et al. (2001) showed that mouse Pss1 used choline, ethanolamine, and serine for base exchange, whereas Pss2 used ethanolamine and serine, but not choline.
PS is normally localized on the cell membrane inner leaflet, but it flips to the cell surface during apoptosis. Grandmaison et al. (2004) showed that Chinese hamster ovary cells deficient in Pss1 and/or Pss2, which resulted in reduction of in vitro serine-exchange activity by as much as 97%, externalized normal amounts of PS during apoptosis. They concluded that normal levels of PSS1 and/or PSS2 are not required to generate the pool of PS externalized during apoptosis.
By assaying solubilized membranes prepared from transfected HeLa cells, Tomohiro et al. (2009) showed that full-length human PSS1 and PSS2 increased serine base-exchange activity 2.9- and 3.5-fold, respectively. Purified PSS1 catalyzed the conversion of both PC and PE into PS, but PSS2 only catalyzed the conversion of PE into PS. In vitro, PSS1 also catalyzed choline and ethanolamine base exchange for the formation of PC and PE, respectively, but PSS2 only catalyzed ethanolamine and serine base exchange. Serine base exchange by both enzymes occurred at a neutral pH optimum and was dependent on Ca(2+). Furthermore, exogenous PS inhibited serine base exchange by PSS1 and PSS2 in membrane fractions of transfected HeLa cells in a dose-dependent manner. However, purified epitope-tagged PSS1, but not PSS2, was activated by PS in the presence of the detergent sucrose monolaurate, suggesting that the mechanism of PS-mediated inhibition differs between PSS1 and PSS2.
By PCR of a panel of human-rodent hybrid cell lines, Nomura et al. (1994) mapped the PTDSS1 gene to chromosome 8.
Sturbois-Balcerzak et al. (2001) mapped the mouse Pss1 gene to chromosome 13B-C1.
In 5 unrelated patients with Lenz-Majewski hyperostotic dwarfism (LMHD; 151050), Sousa et al. (2014) identified 3 different de novo heterozygous missense mutations in the PTDSS1 gene (612792.0001-612792.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in a private exome sequencing database or in public databases. The phenotype was characterized by intellectual disability, progressive sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, distal limb anomalies, and multiple radiographic abnormalities. Patient fibroblasts carrying each of the 3 mutations showed profoundly increased synthesis of phosphatidylserine in the absence of increased protein levels compared to controls, consistent with gain of function. Unlike control cells, PTDSS1 serine-exchange activity was resistant to inhibition by exogenous phosphatidylserine. However, patient cells did not have increased levels of phosphatidylserine, phosphatidylethanolamine, or phosphatidylcholine, indicating tight cellular regulation of phospholipid homeostasis. Expression of the mutations in zebrafish embryos caused a variety of dose-dependent developmental defects in 6 to 40% of embryos 5 days after fertilization. Defects included craniofacial anomalies, trunk angulation, small or absent eyes, and abnormal cartilage. A disturbance in normal apoptosis was not observed in mutant zebrafish. Skin fibroblasts from 2 patients showed cytoplasmic vacuolization possibly containing a storage material, but lipid accumulation was not different from controls. Sousa et al. (2014) noted that phosphatidylserine participates in intracellular signaling and appears to play a role in brain development as well as bone mineralization, suggesting that disrupted phosphatidylserine metabolism likely accounts for the clinical manifestations of LMHD.
Arikketh et al. (2008) found that Pss1 -/- mice were viable and fertile and had normal life spans. Total serine exchange activity in microsomal fractions isolated from Pss1 -/- brain, liver, and heart was reduced up to 85%, but the PS content and Pss2 mRNA levels were unchanged except in Pss1 -/- liver. The rate of axonal extension of Pss1 -/- neurons was normal. Intercrosses of Pss1 -/- and Pss2 -/- mice yielded viable mice with 3 disrupted Pss alleles, but no double-knockout mice were born. In Pss1 +/- Pss2 -/- and Pss1 -/- Pss2 +/- mice, serine exchange activity was reduced by 65 to 91%, and the tissue content of PS and PE was decreased.
In 3 unrelated patients with Lenz-Majewski hyperostotic dwarfism (LMHD; 151050), Sousa et al. (2014) identified a de novo heterozygous c.1058A-G transition in the PTDSS1 gene, resulting in a gln353-to-arg (Q353R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in a private exome sequencing database or in public databases. The patients had previously been reported by Saraiva (2000), Wattanasirichaigoon et al. (2004), and Chrzanowska et al. (1989). Studies in patient fibroblasts showed that end-product inhibition of PTDSS1 by phosphatidylserine was markedly reduced, consistent with a dominant gain of function.
In a boy of Kurd-Turkish origin with Lenz-Majewski hyperostotic dwarfism (151050), Sousa et al. (2014) identified a de novo heterozygous c.805C-T transition in the PTDSS1 gene, resulting in a pro269-to-ser (P269S) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in a private exome sequencing database or in public databases. Studies in patient fibroblasts showed that end-product inhibition of PTDSS1 by phosphatidylserine was markedly reduced, consistent with a dominant gain of function.
In a Czech girl with Lenz-Majewski hyperostotic dwarfism (151050), Sousa et al. (2014) identified a de novo heterozygous c.794T-C transition in the PTDSS1 gene, resulting in a leu265-to-pro (L265P) substitution at a highly conserved residue. The mutation was found by Sanger sequencing and was not present in a private exome sequencing database or in public databases. Studies in patient fibroblasts showed that end-product inhibition of PTDSS1 by phosphatidylserine was markedly reduced, consistent with a dominant gain of function.
Arikketh, D., Nelson, R., Vance, J. E. Defining the importance of phosphatidylserine synthase-1 (PSS1): unexpected viability of PSS1-deficient mice. J. Biol. Chem. 283: 12888-12897, 2008. [PubMed: 18343815] [Full Text: https://doi.org/10.1074/jbc.M800714200]
Chrzanowska, K. H., Fryns, J. P., Krajewska-Walasek, M., Van den Berghe, H., Wisniewski, L. Skeletal dysplasia syndrome with progeroid appearance, characteristic facial and limb anomalies, multiple synostoses, and distinct skeletal changes: a variant example of the Lenz-Majewski syndrome. Am. J. Med. Genet. 32: 470-474, 1989. [PubMed: 2773987] [Full Text: https://doi.org/10.1002/ajmg.1320320407]
Grandmaison, P. A., Nanowski, T. S., Vance, J. E. Externalization of phosphatidylserine during apoptosis does not specifically require either isoform of phosphatidylserine synthase. Biochim. Biophys. Acta 1636: 1-11, 2004. [PubMed: 14984733] [Full Text: https://doi.org/10.1016/j.bbalip.2003.11.004]
Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayasi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly samples cDNA clones from human immature myeloid cell line KG-1. DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995. [PubMed: 7584026] [Full Text: https://doi.org/10.1093/dnares/1.1.27]
Saraiva, J. M. Dysgenesis of corpus callosum in Lenz-Majewski hyperostotic dwarfism. Am. J. Med. Genet. 91: 198-200, 2000. [PubMed: 10756342] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000320)91:3<198::aid-ajmg8>3.0.co;2-4]
Sousa, S. B., Jenkins, D., Chanudet, E., Tasseva, G., Ishida, M., Anderson, G., Docker, J., Ryten, M., Sa, J., Saraiva, J. M., Barnicoat, A., Scott, R., and 9 others. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nature Genet. 46: 70-76, 2014. [PubMed: 24241535] [Full Text: https://doi.org/10.1038/ng.2829]
Stone, S. J., Vance, J. E. Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J. Biol. Chem. 275: 34534-34540, 2000. [PubMed: 10938271] [Full Text: https://doi.org/10.1074/jbc.M002865200]
Sturbois-Balcerzak, B., Stone, S. J., Sreenivas, A., Vance, J. E. Structure and expression of the murine phosphatidylserine synthase-1 gene. J. Biol. Chem. 276: 8205-8212, 2001. [PubMed: 11084049] [Full Text: https://doi.org/10.1074/jbc.M009776200]
Tomohiro, S., Kawaguti, A., Kawabe, Y., Kitada, S., Kuge, O. Purification and characterization of human phosphatidylserine synthases 1 and 2. Biochem. J. 418: 421-429, 2009. [PubMed: 19014349] [Full Text: https://doi.org/10.1042/BJ20081597]
Wattanasirichaigoon, D., Visudtibhan, A., Jaovisidha, S., Laothamatas, J., Chunharas, A. Expanding the phenotypic spectrum of Lenz-Majewski syndrome: facial palsy, cleft palate and hydrocephalus. Clin. Dysmorph. 13: 137-142, 2004. [PubMed: 15194948] [Full Text: https://doi.org/10.1097/01.mcd.0000127468.11641.b7]