Alternative titles; symbols
HGNC Approved Gene Symbol: PGAP2
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:3,797,724-3,826,371 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Hyperphosphatasia with impaired intellectual development syndrome 3 | 614207 | Autosomal recessive | 3 |
Glycosylphosphatidylinositol (GPI) modification of plasma membrane proteins occurs in the endoplasmic reticulum (ER), and GPI-anchored proteins are incorporated into rafts in the Golgi during their transport to the cell surface. PGAP2 appears to be involved in maturation of the GPI anchor on GPI-anchored proteins (Tashima et al., 2006).
By screening an M426 human embryonic fibroblast cell line with rat Frag1, Lorenzi et al. (1999) cloned PGAP2, which they called FRAG1. The deduced 316-amino acid protein has 2 N-terminal FRAG1 homology (FH) domains and 4 possible isoprenylation signals. Hydropathy analysis suggested that FRAG1 has 7 transmembrane segments. Human and rat FRAG1 share 92% amino acid identity, but the rat protein has only 1 FH domain. Northern blot analysis detected variable expression of a 2.0-kb FRAG1 transcript in all 16 tissues examined, with highest expression in testis and pancreas, and lowest expression in brain and thymus. A transcript of about 3.2 kb was also detected in several tissues, predominantly pancreas, spleen, and prostate. FRAG1 was also detected in a number of tumor cell lines at a level comparable to that observed in normal tissues.
By database analysis and cloning using rat and hamster cDNA libraries, Tashima et al. (2006) identified human, rat, and hamster cDNAs encoding a 254-amino acid PGAP2 protein. They also identified a splice variant in human and hamster that encodes a 250-amino acid isoform lacking a VSQE sequence. Rat Pgap2 localized to Golgi in transfected NRK cells.
Umemura et al. (2007) reported that the 953-amino acid yeast Cwh43 protein shares homology with human PGAP2 in its N-terminal region and with human CWH43 (618561) in its C-terminal region, which contains 18 potential transmembrane domains. Yeast Cwh43 localized to ER membranes in yeast cells.
Hansen et al. (2013) stated that the PGAP2 gene encodes 16 different RNA transcripts, 8 of which encode different isoforms and 8 that are noncoding RNA. Isoform 8, which is 254 amino acids long and contains 5 alpha-helix domains embedded in the Golgi membrane, is believed to be the biologically active isoform. The N terminus is in the cytoplasm and the C terminus is in the Golgi lumen.
Tashima et al. (2006) found that transfected CHO cells lacking Pgap2 were deficient in cell surface expression of the human GPI-anchored proteins CD59 (107271) and CD55 (125240). Cotransfection of rat Pgap2 or the human or hamster variant encoding the short PGAP2 isoform restored CD59 surface expression. GPI-anchored proteins appeared to traffic normally through the ER and Golgi, but they were secreted upon arrival at the plasma membrane via phospholipid D (see 602382)-like activity. The secreted proteins showed an altered GPI anchor. Tashima et al. (2006) proposed that remodeling of the GPI anchor occurs in GPI-anchored proteins, and that in Pgap2-deficient cells, this remodeling is defective, resulting in GPI-anchored proteins that are sensitive to cleavage then secretion from the plasma membrane.
Umemura et al. (2007) found that yeast cells lacking Cwh43 had a defect in remodeling the lipid moieties of GPI anchors from a diacylglycerol type to a ceramide type. Further analyses revealed that the C-terminal region of Cwh43 was essential for GPI lipid remodeling, whereas the N-terminal region of Cwh43 associated with the C-terminal region and enhanced ceramide formation by the C-terminal region. Mouse C130090K23, the ortholog of human CWH43, could remodel lipid moieties in GPI-anchored proteins to ceramides and rescue the phenotype of yeast with Cwh43 deletion, similar to the C-terminal region of yeast Cwh43. Frag1, the ortholog of human PGAP2, enhanced lipid remodeling by C130090K23, but was unable to rescue the phenotype of yeast with Cwh43 deletion, similar to the N-terminal region of yeast Cwh43. Immunoprecipitation analysis confirmed that mouse C130090K23 and Frag1 associated with each other.
Lorenzi et al. (1999) determined that the PGAP2 gene contains 6 exons and spans over 7 kb. The tandem FH domains in the FRAG1 protein are encoded by exons 1 and 2.
Using FISH and radiation hybrid analysis, Lorenzi et al. (1999) mapped the PGAP2 gene to chromosome 11p15.5.
In affected members of 2 unrelated consanguineous families with hyperphosphatasia with impaired intellectual develpment syndrome-3 (HPMRS3; 614207), Hansen et al. (2013) identified 2 different homozygous missense mutations in the PGAP2 gene (615187.0001 and 615187.0002, respectively). In vitro functional expression studies showed that the mutant alleles were hypomorphic and caused decreased enzyme activity. Hansen et al. (2013) commented that the disorder due to PGAP2 mutations can be viewed as part of a disease family representing a spectrum of disorders due to mutations in genes involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Mutations in genes earlier in the pathway appear to cause a more severe phenotype, including dysmorphic features (e.g., MCAHS1, 614080), than mutations in genes that act later in the pathway.
Among 13 individuals with intellectual disability and increased serum alkaline phosphatase who were screened for mutations in genes encoding proteins in the GPI-anchor biosynthesis pathway, Krawitz et al. (2013) found that 2 unrelated patients carried biallelic missense mutations in the PGAP2 gene (615187.0003-615187.0005). In vitro studies showed that the mutations caused decreased enzyme activity.
In 3 affected members of a consanguineous Syrian family (MR043) with autosomal recessive hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3; 614207), originally reported by Abou Jamra et al. (2011), Hansen et al. (2013) identified a homozygous c.296A-G transition in the PGAP2 gene, resulting in a tyr99-to-cys (Y99C) substitution between transmembrane segments 1 and 2 in the Golgi lumen. The mutation, which was found by exome sequencing of the linked region on chromosome 11p15, was confirmed by Sanger sequencing and segregated with the disorder in the family. In vitro functional expression studies in CHO cells showed that the mutant protein was expressed but had significantly decreased activity compared to wildtype. Patient lymphoblastoid cells showed essentially normal expression of the GPI-anchored proteins DAF (125240) and CD59 (107271), supporting a hypomorphic effect of the Y99C mutation.
In affected members of a consanguineous Pakistani family (MR5) with autosomal recessive hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3; 614207), originally reported by Rehman et al. (2011), Hansen et al. (2013) identified a homozygous c.530G-C transversion in the PGAP2 gene, resulting in an arg177-to-pro (R177P) substitution between transmembrane segments 3 and 4 in the Golgi lumen. The mutation, which was found by exome sequencing of the linked region on chromosome 11p15, was confirmed by Sanger sequencing and segregated with the disorder in the family. In vitro functional expression studies in CHO cells showed that the mutant protein was expressed but had significantly decreased activity compared to wildtype. Patient lymphoblastoid cells showed essentially normal expression of the GPI-anchored proteins DAF (125240) and CD59 (107271), supporting a hypomorphic effect of the R177P mutation.
In a Turkish boy, born of consanguineous parents, autosomal recessive hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3; 614207), Krawitz et al. (2013) identified a homozygous c.380T-C transition in the PGAP2 gene, resulting in a leu127-to-ser (L127S) substitution at a highly conserved residue. The mutation segregated with the disorder in the family. In vitro functional expression studies showed that the mutant protein had decreased activity compared to wildtype.
In a 28-year-old Finnish woman with mild hyperphosphatasia with impaired intellectual development syndrome (HPMRS3; 614207), Krawitz et al. (2013) identified compound heterozygosity for 2 mutations in the PGAP2 gene: a c.46C-T transition resulting in an arg16-to-trp (R16W) substitution, and a c.479C-T transition resulting in a thr160-to-ile (T160I; 615187.0005) substitution. Both mutations occurred at highly conserved residues. In vitro functional expression studies showed that the mutant proteins had decreased activity compared to wildtype. Higher residual activity of R16W may explain the milder phenotype in this patient.
For discussion of the thr160-to-ile (T160I) mutation in the PGAP2 gene that was found in compound heterozygous state in a patient with hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3; 614207) by Krawitz et al. (2013), see 615187.0004.
Abou Jamra, R. A., Wohlfart, S., Zweier, M., Uebe, S., Priebe, L., Ekici, A., Giesebrecht, S., Abboud, A., Al Khateeb, M. A., Fakher, M., Hamdan, S., Ismael, A., Muhammad, S., Nothen, M. M., Schumacher, J., Reis, A. Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity. Europ. J. Hum. Genet. 19: 1161-1166, 2011. [PubMed: 21629298] [Full Text: https://doi.org/10.1038/ejhg.2011.98]
Hansen, L., Tawamie, H., Murakami, Y., Mang, Y., Rehman, S., Buchert, R., Schaffer, S., Muhammad, S., Bak, M., Nothen, M. M., Bennett, E. P., Maeda, Y., Aigner, M., Reis, A., Kinoshita, T., Tommerup, N., Baig, S. M., Abou Jamra, R. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. Am. J. Hum. Genet. 92: 575-583, 2013. [PubMed: 23561846] [Full Text: https://doi.org/10.1016/j.ajhg.2013.03.008]
Krawitz, P. M., Murakami, Y., Riess, A., Hietala, M., Kruger, U., Zhu, N., Kinoshita, T., Mundlos, S., Hecht, J., Robinson, P. N., Horn, D. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. Am. J. Hum. Genet. 92: 584-589, 2013. [PubMed: 23561847] [Full Text: https://doi.org/10.1016/j.ajhg.2013.03.011]
Lorenzi, M. V., Castagnino, P., Aaronson, D. C., Lieb, D. C., Lee, C. C., Keck, C. L., Popescu, N. C., Miki, T. Human FRAG1 encodes a novel membrane-spanning protein that localizes to chromosome 11p15.5, a region of frequent loss of heterozygosity in cancer. Genomics 62: 59-66, 1999. [PubMed: 10585768] [Full Text: https://doi.org/10.1006/geno.1999.5980]
Rehman, S., Baig, S. M., Eiberg, H., Rehman, S., Ahmad, I., Malik, N. A., Tommerup, N., Hansen, L. Autozygosity mapping of a large consanguineous Pakistani family reveals a novel non-syndromic autosomal recessive mental retardation locus on 11p15-tel. Neurogenetics 12: 247-251, 2011. [PubMed: 21643797] [Full Text: https://doi.org/10.1007/s10048-011-0286-5]
Tashima, Y., Taguchi, R., Murata, C., Ashida, H., Kinoshita, T., Maeda, Y. PGAP2 is essential for correct processing and stable expression of GPI-anchored proteins. Molec. Biol. Cell 17: 1410-1420, 2006. [PubMed: 16407401] [Full Text: https://doi.org/10.1091/mbc.e05-11-1005]
Umemura, M., Fujita, M., Yoko-o, T., Fukamizu, A., Jigami, Y. Saccharomyces cerevisiae CWH43 is involved in the remodeling of the lipid moiety of GPI anchors to ceramides. Molec. Biol. Cell 18: 4304-4316, 2007. [PubMed: 17761529] [Full Text: https://doi.org/10.1091/mbc.e07-05-0482]