Alternative titles; symbols
HGNC Approved Gene Symbol: PGAP3
Cytogenetic location: 17q12 Genomic coordinates (GRCh38) : 17:39,671,122-39,688,057 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | Hyperphosphatasia with impaired intellectual development syndrome 4 | 615716 | Autosomal recessive | 3 |
The PGAP3 gene encodes a glycophosphatidylinositol (GPI)-specific phospholipase A2 that is expressed in the Golgi. The enzyme is involved in fatty acid GPI remodeling that is critical for proper association between GPI-anchored proteins and lipid rafts (summary by Howard et al., 2014).
Nezu et al. (2002) identified the PERLD1 gene, which they called CAB2, in a region of chromosome 17 amplified in breast and gastric cancers, and they obtained a full-length CAB2 cDNA by screening a breast cancer cell line cDNA library. The deduced 319-amino acid protein contains several transmembrane domains. CAB2 was ubiquitously expressed, with highest levels in adult thyroid and placenta and in all 4 fetal tissues examined. Fluorescence-tagged CAB2 accumulated in cytoplasmic vesicles in a transfected human breast cancer cell line. By database analysis, Nezu et al. (2002) identified CAB2 homologs in yeast, worm, fly, and plant.
By database analysis, Katoh and Katoh (2003) identified mouse and human PERLD1, which they designated MGC9753. Human MGC9753 contains 2 ORFs, but only the first is conserved in mouse. The human and mouse MGC9753 proteins contain 320 amino acids and share 85% amino acid identity. Both have an N-terminal signal peptide, followed by an extracellular 6-cysteine domain, 7 transmembrane domains, and an N-glycosylation site at asn40. Human MGC9753 shares 90.6% identity with the CAB2 protein reported by Nezu et al. (2002), which diverges in the central region and lacks transmembrane domain-3 due to a frameshift. Katoh and Katoh (2003) concluded that CAB2 is an aberrant protein that may accumulate in vesicles due to sorting error.
Katoh and Katoh (2003) determined that the PERLD1 gene contains 8 exons and spans about 17 kb.
By genomic sequence analysis, Nezu et al. (2002) mapped the PERLD1 gene to a region of chromosome 17q12 that is amplified in breast and gastric cancers.
In 5 patients from 3 families with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), Howard et al. (2014) identified homozygous or compound heterozygous mutations in the PGAP3 gene (611801.0001-611801.0004). The mutation in the first family was found by exome sequencing. Transfection of wildtype PGAP3 into CHO cells that lack both PGAP3 and PGAP2 (615187) restored the first step in fatty acid remodeling, but the second step remained defective, leading to a reduction in surface levels of GPI-anchored proteins. In vitro functional expression studies in CHO cells showed that the mutant PGAP3 proteins had either no or only residual enzymatic activity. The phenotype was characterized by severely delayed psychomotor development, impaired intellectual development, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies showed increased serum alkaline phosphatase.
In 9 patients from 5 Saudi families with HPMRS4, Maddirevula et al. (2018) identified a his284-to-tyr mutation (H284Y; 611801.0005) in the PGAP3 gene.
In 14 patients from 8 Arab families with HPMRS4, Balobaid et al. (2018) identified homozygosity for 3 missense mutations in the PGAP3 gene: H284Y, H284R (611801.0006), and S107L. Seven of the families were consanguineous. The mutations, which were found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in all families for which DNA was available from the parents.
In 2 sibs from Turkey, born to consanguineous parents, with HPMRS4, Akgun Dogan et al. (2019) identified homozygosity for a nonsense mutation in the PGAP3 gene (Y169X; 611801.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 3 sibs, born of consanguineous Pakistani parents with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), Howard et al. (2014) identified a homozygous c.275G-A transition in the PGAP3 gene, resulting in a gly92-to-asp (G92D) substitution at a highly conserved residue in a juxtamembrane position on the luminal side. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases, or in 108 ethnically matched controls. In vitro functional expression studies in CHO cells showed that the mutant G92D protein had almost no or absent enzyme activity. Electrophoresis and immunoblotting studies showed that the G92D protein was full-sized, had normally matured N-glycan, and localized to the Golgi, similar to wildtype.
In a 10-year-old Caucasian American girl with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), originally reported (patient 4) by Thompson et al. (2012), Howard et al. (2014) identified compound heterozygous mutations in the PGAP3 gene: a 1-bp duplication (c.439dupC), predicted to result in a frameshift and premature termination (Leu147ProfsTer16), and a c.914A-G transition, resulting in an asp305-to-gly (D305G; 611801.0003) substitution at a highly conserved residue in the cytoplasmic tail. The unaffected parents were heterozygous for one of the mutations. In vitro functional expression studies in CHO cells showed that the mutant D305G protein had some residual enzyme activity, whereas the c.439dupC mutant had no residual enzyme activity, and was likely degraded by nonsense-mediated mRNA decay. Electrophoresis and immunoblotting studies showed that the D305G protein had only immature ER-form N-glycan and did not localize properly to the Golgi, but was retained in the ER. Flow cytometric analysis of patient cells showed a reduction in the cell surface levels of GPI-anchored proteins.
For discussion of the asp305-to-gly (D305G) mutation in the PGAP3 gene that was found in compound heterozygous state in a patient with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716) by Howard et al. (2014), see 611801.0002.
In a 2-year-old girl, born of consanguineous Saudi Arabian parents, with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), Howard et al. (2014) identified a homozygous c.314C-G transversion in the PGAP3 gene, resulting in a pro105-to-arg (P105R) substitution at a highly conserved residue in the first transmembrane domain. The unaffected parents were heterozygous for the mutation, which was not found in 52 Arab controls or in the Exome Variant Server database. In vitro functional expression studies in CHO cells showed that the mutant P105R protein had low residual enzyme activity. Electrophoresis and immunoblotting studies showed that the P105R protein had only immature ER-form N-glycan and did not localize properly to the Golgi, but was retained in the ER.
In 9 patients from 5 Saudi families with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), Maddirevula et al. (2018) identified homozygosity for a founder c.850C-T transition (c.850C-T, NM_033419.3) in the PGAP3 gene that resulted in a histidine-to-tyrosine substitution at codon 284 (H284Y). This variant was absent from the gnomAD database on April 14, 2020 (Hamosh, 2020).
In 4 patients from 2 consanguineous Saudi families with HPMRS4, Balobaid et al. (2018) identified homozygosity for the H284Y mutation in the PGAP3 gene. The authors proposed that this mutation might represent a founder mutation warranting targeted genetic testing once clinical suspicion of HPMRS4 is raised.
In 8 patients from 5 unrelated families (3 from Qatar and 2 from Oman) with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716) Balobaid et al. (2018) identified homozygosity for a c.851A-G transition (c.851A-G, NM_033419) in exon 7 of the PGAP3 gene, resulting in a his284-to-arg (H284R) substitution.
In 2 sibs from Turkey, born to consanguineous parents, with hyperphosphatasia with impaired intellectual development syndrome-4 (HPMRS4; 615716), Akgun Dogan et al. (2019) identified homozygosity for a c.507C-A transversion (c.507C-A, NM_033419.4) in the PGAP3 gene, resulting in a tyr169-to-ter (Y169X) substitution predicted to lack the 5 transmembrane domains of the protein. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was not present in an in-house database comprising 380 unrelated Turkish individuals. Functional studies were not performed.
Akgun Dogan, O., Demir, G. U., Kosukcu, C., Takiran, E. Z., Simsek-Kiper, P. O., Utine, G. E., Alikasifoglu, M., Boduroglu, K. Hyperphosphatasia with mental retardation syndrome type 4 in two siblings--expanding the phenotypic and mutational spectrum. Europ. J. Med. Genet. 62: 103535, 2019. [PubMed: 30217754] [Full Text: https://doi.org/10.1016/j.ejmg.2018.09.002]
Balobaid, A., Ben-Omran, T., Ramzan, K., Altassan, R., Almureikhi, M., Musa, S., Al-Hashmi, N., Al-Owain, M., Al-Zaidan H., Al-Hassnan, Z., Imtiaz, F., Al-Sayed, M. Delineating the phenotypic spectrum of hyperphosphatasia with mental retardation syndrome 4 in 14 patients of Middle-Eastern origin. Am. J. Med. Genet. 176A: 2850-2857, 2018. [PubMed: 30345601] [Full Text: https://doi.org/10.1002/ajmg.a.40627]
Hamosh, A. Personal Communication. Baltimore, Md. 04/14/2020.
Howard, M. F., Murakami, Y., Pagnamenta, A. T., Daumer-Haas, C., Fischer, B., Hecht, J., Keays, D. A., Knight, S. J. L., Kolsch, U., Kruger, U., Leiz, S., Maeda, Y., and 9 others. Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. Am. J. Hum. Genet. 94: 278-287, 2014. [PubMed: 24439110] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.012]
Katoh, M., Katoh, M. MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein (sic) domain. Int. J. Oncol. 22: 1369-1374, 2003. [PubMed: 12739007]
Maddirevula, S., Alsahli, S., Alhabeeb, L., Patel, N., Alzahrani, F., Shamseldin, H. E., Anazi, S., Ewida, N., Alsaif, H. S., Mohamed, J. Y., Alazami, A. M., Ibrahim, N., and 44 others. Expanding the phenome and variome of skeletal dysplasia. Genet. Med. 20: 1609-1616, 2018. [PubMed: 29620724] [Full Text: https://doi.org/10.1038/gim.2018.50]
Nezu, M., Nishigaki, M., Ishizuka, T., Kuwahara, Y., Tanabe, C., Aoyagi, K., Sakamoto, H., Saito, Y., Yoshida, T., Sasaki, H., Terada, M. Identification of the CAB2/hCOS16 gene required for the repair of DNA double-strand breaks on a core amplified region of the 17q12 locus in breast and gastric cancers. Jpn. J. Cancer Res. 93: 1183-1186, 2002. [PubMed: 12460457] [Full Text: https://doi.org/10.1111/j.1349-7006.2002.tb01221.x]
Thompson, M. D., Roscioli, T., Marcelis, C., Nezarati, M. M., Stolte-Dijkstra, I., Sharom, F. J., Lu, P., Phillips, J. A., Sweeney, E., Robinson, P. N., Krawitz, P., Yntema, H. G., Andrade, D. M., Brunner, H. G., Cole, D. E. C. Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome). Am. J. Med. Genet. 158A: 553-558, 2012. [PubMed: 22315194] [Full Text: https://doi.org/10.1002/ajmg.a.35202]