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Gene Review

PIGA  -  phosphatidylinositol glycan anchor...

Homo sapiens

Synonyms: GPI3, GlcNAc-PI synthesis protein, MCAHS2, PIG-A, PNH1, ...
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Disease relevance of PIGA

  • As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells [1].
  • This benign clonal disease is caused by abnormalities of the X-linked phosphatidylinositol glycan class A (PIGA) gene and is associated with cytopenias and thrombosis [2].
  • We have carried out a molecular and functional analysis of the PIG-A gene in four cell lines deficient in GPI-linked proteins, obtained by Epstein-Barr virus (EBV) transformation of affected B-lymphocytes from PNH patients [3].
  • By isolating genomic clones from a human phage library we now show that the PIG-A gene consists of six exons (the first of which is non-coding) spanning 17 kb of DNA, and we have mapped the gene to chromosomal position Xp22 [4].
  • Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone [5].

High impact information on PIGA

  • The structure of the cloned complementary DNA was analyzed by nucleotide sequencing, and its function was assessed on the basis of its ability to restore to normal the abnormal phenotype of a PIG-A-deficient cell line after transfection [6].
  • Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria [6].
  • Recently, we demonstrated that a gene termed PIG-A (for phosphatidylinositol glycan class A), a component of glycosyl-phosphatidylinositol biosynthesis, was responsible for PNH in two patients [6].
  • Here we report that PIG-A, which participates in the early step of GPI anchor biosynthesis, is the gene responsible for paroxysmal nocturnal hemoglobinuria [7].
  • We localized PIG-A to the X chromosome, which accounts for expression of the recessive phenotype of the somatic mutation and the fact that the same one of the multiple biosynthetic steps is affected in all patients so far characterized [7].

Chemical compound and disease context of PIGA

  • A somatic mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene causes the loss of glycosyl phosphatidylinositol (GPI)-linked proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria [8].

Biological context of PIGA


Anatomical context of PIGA

  • Single cell cloning of purged and sorted GPI-anchor- HCT116 cells and sequencing of the PIGA gene in each clone uniformly showed mutations [9].
  • Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell (HSC) disorder in which an acquired somatic mutation of the X-linked PIGA gene results in a deficiency in GPI-anchored surface proteins [12].
  • The PIGA mutation results in absence or marked deficiency of more than a dozen proteins on PNH blood cells [13].
  • In PNH, haematopoietic stem cells that harbour PIGA mutations give rise to blood elements that are unable to synthesize glycosylphosphatidylinositol (GPI) anchors [14].
  • Affected granulocytes and B lymphocytes had the same somatic mutation of PIG-A, indicating their clonal origin from a multipotential hematopoietic stem cell [7].

Associations of PIGA with chemical compounds

  • Previously, an X-linked gene PIGA (phosphatidylinositol glycan class A), which participates in the first step of the biosynthesis, was shown to be mutated in abnormal cells from all 60 patients with PNH [15].
  • Here we demonstrate 1) that PIG-A is an ER transmembrane protein with a large cytoplasmic domain that has homology to a bacterial GlcNAc transferase and a small lumenal domain; 2) that PIG-H is a cytoplasmically oriented, ER-associated protein; and 3) that they form a protein complex [16].
  • The cytosolic part of PIG-A/GPI3 has a two-domain alpha/beta/alpha-layered structure; it is suggested that its C-terminal subsegment binds UDP-GlcNAc whereas the N-terminal domain interacts with the phosphatidylinositol moiety [17].
  • All patients with PNH studied so far have a somatic mutation in an X-linked gene, called PIG-A (phosphatidyl inositol glycan complementation group A), which encodes for a protein involved in the biosynthesis of the glycosyl phosphatidylinositol (GPI) molecule, that serves as an anchor for many cell surface proteins [18].
  • The PIG-A gene maps to Xp22.1 and is required for the transfer of N-acetyl glucosamine to phosphoinositol, an early step in the production of the GPI anchor [19].

Regulatory relationships of PIGA


Other interactions of PIGA

  • GPI-GnT is a uniquely complex glycosyltransferase, consisting of at least four proteins, PIG-A, PIG-H, PIG-C and GPI1 [22].
  • YAC contig construction allowed the following locus order to be established: Xpter-DXS16-DXS69E-DXS414-XE59 - DXS9 - (GLRA2, DXS987) - (PIGA, DXS207) - DXS1053-DXS197-(GRPR,DXS43)-CALB3-DXS14 16- DXS1317 - DXS1195 - DXS418 - DXS257 - (PHKA2, DXS999)-DXS443-DXS1229-Xcen [23].
  • We report pairs of oligonucleotide primers for polymerase chain reaction that should be useful to amplify and analyze various regions of the PIG-A gene in patients with PNH [24].
  • Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP [25].
  • The purpose of our study was to clarify the distribution of PIG-A gene abnormalities among various cell lineages during differentiation and maturation in PNH patients.The expression of CD16b or CD59 in peripheral blood granulocytes or cultured erythroblasts from three Japanese PNH patients was analyzed using flow cytometry [26].

Analytical, diagnostic and therapeutic context of PIGA


  1. Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Almeida, A.M., Murakami, Y., Layton, D.M., Hillmen, P., Sellick, G.S., Maeda, Y., Richards, S., Patterson, S., Kotsianidis, I., Mollica, L., Crawford, D.H., Baker, A., Ferguson, M., Roberts, I., Houlston, R., Kinoshita, T., Karadimitris, A. Nat. Med. (2006) [Pubmed]
  2. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Krauss, J.S. Ann. Clin. Lab. Sci. (2003) [Pubmed]
  3. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. Bessler, M., Mason, P.J., Hillmen, P., Miyata, T., Yamada, N., Takeda, J., Luzzatto, L., Kinoshita, T. EMBO J. (1994) [Pubmed]
  4. Genomic organization of the X-linked gene (PIG-A) that is mutated in paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene mapped to 12q21. Bessler, M., Hillmen, P., Longo, L., Luzzatto, L., Mason, P.J. Hum. Mol. Genet. (1994) [Pubmed]
  5. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Inoue, N., Izui-Sarumaru, T., Murakami, Y., Endo, Y., Nishimura, J., Kurokawa, K., Kuwayama, M., Shime, H., Machii, T., Kanakura, Y., Meyers, G., Wittwer, C., Chen, Z., Babcock, W., Frei-Lahr, D., Parker, C.J., Kinoshita, T. Blood (2006) [Pubmed]
  6. Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. Miyata, T., Yamada, N., Iida, Y., Nishimura, J., Takeda, J., Kitani, T., Kinoshita, T. N. Engl. J. Med. (1994) [Pubmed]
  7. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Takeda, J., Miyata, T., Kawagoe, K., Iida, Y., Endo, Y., Fujita, T., Takahashi, M., Kitani, T., Kinoshita, T. Cell (1993) [Pubmed]
  8. FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hematopoietic stem cells in the bone marrow. Keller, P., Payne, J.L., Tremml, G., Greer, P.A., Gaboli, M., Pandolfi, P.P., Bessler, M. J. Exp. Med. (2001) [Pubmed]
  9. Glycophosphatidylinositol-anchored protein deficiency as a marker of mutator phenotypes in cancer. Chen, R., Eshleman, J.R., Brodsky, R.A., Medof, M.E. Cancer Res. (2001) [Pubmed]
  10. Structures and chromosomal localizations of the glycosylphosphatidylinositol synthesis gene PIGC and its pseudogene PIGCP1. Hong, Y., Ohishi, K., Inoue, N., Endo, Y., Fujita, T., Takeda, J., Kinoshita, T. Genomics (1997) [Pubmed]
  11. Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1 between the PIGA and the GRPR genes. Rocchigiani, M., Lestingi, M., Luddi, A., Orlandini, M., Franco, B., Rossi, E., Ballabio, A., Zuffardi, O., Oliviero, S. Genomics (1998) [Pubmed]
  12. A SIN lentiviral vector containing PIGA cDNA allows long-term phenotypic correction of CD34+-derived cells from patients with paroxysmal nocturnal hemoglobinuria. Robert, D., Mahon, F.X., Richard, E., Etienne, G., de Verneuil, H., Moreau-Gaudry, F. Mol. Ther. (2003) [Pubmed]
  13. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Brodsky, R.A., Mukhina, G.L., Li, S., Nelson, K.L., Chiurazzi, P.L., Buckley, J.T., Borowitz, M.J. Am. J. Clin. Pathol. (2000) [Pubmed]
  14. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia. Mukhina, G.L., Buckley, J.T., Barber, J.P., Jones, R.J., Brodsky, R.A. Br. J. Haematol. (2001) [Pubmed]
  15. Structure and chromosomal localization of the GPI-anchor synthesis gene PIGF and its pseudogene psi PIGF. Ohishi, K., Inoue, N., Endo, Y., Fujita, T., Takeda, J., Kinoshita, T. Genomics (1995) [Pubmed]
  16. PIG-A and PIG-H, which participate in glycosylphosphatidylinositol anchor biosynthesis, form a protein complex in the endoplasmic reticulum. Watanabe, R., Kinoshita, T., Masaki, R., Yamamoto, A., Takeda, J., Inoue, N. J. Biol. Chem. (1996) [Pubmed]
  17. Enzymes and auxiliary factors for GPI lipid anchor biosynthesis and post-translational transfer to proteins. Eisenhaber, B., Maurer-Stroh, S., Novatchkova, M., Schneider, G., Eisenhaber, F. Bioessays (2003) [Pubmed]
  18. The molecular basis of paroxysmal nocturnal hemoglobinuria. Rosti, V. Haematologica (2000) [Pubmed]
  19. The PIG-A gene somatic mutation responsible for paroxysmal nocturnal hemoglobinuria. Rotoli, B., Boccuni, P. Haematologica (1995) [Pubmed]
  20. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Nagakura, S., Ishihara, S., Dunn, D.E., Nishimura, J., Kawaguchi, T., Horikawa, K., Hidaka, M., Kagimoto, T., Eto, N., Mitsuya, H., Kinoshita, T., Young, N.S., Nakakuma, H. Blood (2002) [Pubmed]
  21. Paroxysmal nocturnal hemoglobinuria: analysis of the effects of mutant PIG-A on gene expression. Kanai, N., Vreeke, T.M., Parker, C.J. Am. J. Hematol. (1999) [Pubmed]
  22. Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P and is regulated by DPM2. Watanabe, R., Murakami, Y., Marmor, M.D., Inoue, N., Maeda, Y., Hino, J., Kangawa, K., Julius, M., Kinoshita, T. EMBO J. (2000) [Pubmed]
  23. A 6-Mb YAC contig in Xp22.1-p22.2 spanning the DXS69E, XE59, GLRA2, PIGA, GRPR, CALB3, and PHKA2 genes. Alitalo, T., Francis, F., Kere, J., Lehrach, H., Schlessinger, D., Willard, H.F. Genomics (1995) [Pubmed]
  24. Characterization of genomic PIG-A gene: a gene for glycosylphosphatidylinositol-anchor biosynthesis and paroxysmal nocturnal hemoglobinuria. Iida, Y., Takeda, J., Miyata, T., Inoue, N., Nishimura, J., Kitani, T., Maeda, K., Kinoshita, T. Blood (1994) [Pubmed]
  25. Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Hanaoka, N., Kawaguchi, T., Horikawa, K., Nagakura, S., Mitsuya, H., Nakakuma, H. Blood (2006) [Pubmed]
  26. The distribution of PIG-A gene abnormalities in paroxysmal nocturnal hemoglobinuria granulocytes and cultured erythroblasts. Noji, H., Shichishima, T., Saitoh, Y., Kai, T., Yamamoto, T., Ogawa, K., Okamoto, M., Ikeda, K., Maruyama, Y. Exp. Hematol. (2001) [Pubmed]
  27. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Mortazavi, Y., Merk, B., McIntosh, J., Marsh, J.C., Schrezenmeier, H., Rutherford, T.R. Blood (2003) [Pubmed]
  28. Mutations within the Piga gene in patients with paroxysmal nocturnal hemoglobinuria. Ware, R.E., Rosse, W.F., Howard, T.A. Blood (1994) [Pubmed]
  29. Characterisation of the enzymatic complex for the first step in glycosylphosphatidylinositol biosynthesis. Tiede, A., Nischan, C., Schubert, J., Schmidt, R.E. Int. J. Biochem. Cell Biol. (2000) [Pubmed]
  30. CD59-deficient blood cells and PIG-A gene abnormalities in Japanese patients with aplastic anaemia. Azenishi, Y., Ueda, E., Machii, T., Nishimura, J., Hirota, T., Shibano, M., Nakao, S., Kinoshita, T., Mizoguchi, H., Kitani, T. Br. J. Haematol. (1999) [Pubmed]
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