ID PIGA_HUMAN Reviewed; 484 AA. AC P37287; B4E0V2; Q16025; Q16250; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 27-MAR-2024, entry version 200. DE RecName: Full=Phosphatidylinositol N-acetylglucosaminyltransferase subunit A {ECO:0000305}; DE EC=2.4.1.198 {ECO:0000305|PubMed:16162815}; DE AltName: Full=GlcNAc-PI synthesis protein; DE AltName: Full=Phosphatidylinositol-glycan biosynthesis class A protein; DE Short=PIG-A; GN Name=PIGA {ECO:0000312|HGNC:HGNC:8957}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=7680492; DOI=10.1126/science.7680492; RA Miyata T., Takeda J., Iida Y., Yamada N., Inoue N., Takahashi M., Maeda K., RA Kitani T., Kinoshita T.; RT "The cloning of PIG-A, a component in the early step of GPI-anchor RT biosynthesis."; RL Science 259:1318-1320(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=8081362; DOI=10.1093/hmg/3.5.751; RA Bessler M., Hillmen P., Longo L., Luzzatto L., Mason P.J.; RT "Genomic organization of the X-linked gene (PIG-A) that is mutated in RT paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene RT mapped to 12q21."; RL Hum. Mol. Genet. 3:751-757(1994). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=8193350; RA Iida Y., Takeda J., Miyata T., Inoue N., Nishimura J., Kitani T., Maeda K., RA Kinoshita T.; RT "Characterization of genomic PIG-A gene: a gene for RT glycosylphosphatidylinositol-anchor biosynthesis and paroxysmal nocturnal RT hemoglobinuria."; RL Blood 83:3126-3131(1994). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RX PubMed=8081230; RA Yu J., Nagarajan S., Ueda E., Knez J.J., Petersen R.B., Medof M.E.; RT "Characterization of alternatively spliced PIG-A transcripts in normal and RT paroxysmal nocturnal hemoglobinuria cells."; RL Braz. J. Med. Biol. Res. 27:195-201(1994). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 301-420, AND INVOLVEMENT IN PNH1. RX PubMed=8500164; DOI=10.1016/0092-8674(93)90250-t; RA Takeda J., Miyata T., Kawagoe K., Iida Y., Endo Y., Fujita T., RA Takahashi M., Kitani T., Kinoshita T.; RT "Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A RT gene in paroxysmal nocturnal hemoglobinuria."; RL Cell 73:703-711(1993). RN [9] RP COMPONENT OF GPI-GNT COMPLEX, AND INTERACTION WITH PIGQ. RX PubMed=9463366; DOI=10.1093/emboj/17.4.877; RA Watanabe R., Inoue N., Westfall B., Taron C.H., Orlean P., Takeda J., RA Kinoshita T.; RT "The first step of glycosylphosphatidylinositol biosynthesis is mediated by RT a complex of PIG-A, PIG-H, PIG-C and GPI1."; RL EMBO J. 17:877-885(1998). RN [10] RP INTERACTION WITH PIGC; PIGH; PIGP; PIGQ; PIGY AND DPM2, COMPONENT OF RP GPI-GNT COMPLEX, CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=16162815; DOI=10.1091/mbc.e05-08-0743; RA Murakami Y., Siripanyaphinyo U., Hong Y., Tashima Y., Maeda Y., RA Kinoshita T.; RT "The initial enzyme for glycosylphosphatidylinositol biosynthesis requires RT PIG-Y, a seventh component."; RL Mol. Biol. Cell 16:5236-5246(2005). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [12] RP INVOLVEMENT IN MCAHS2, VARIANT MCAHS2 412-ARG--ARG-484 DEL, AND RP CHARACTERIZATION OF VARIANT MCAHS2 412-ARG--ARG-484 DEL. RX PubMed=22305531; DOI=10.1016/j.ajhg.2011.11.031; RA Johnston J.J., Gropman A.L., Sapp J.C., Teer J.K., Martin J.M., Liu C.F., RA Yuan X., Ye Z., Cheng L., Brodsky R.A., Biesecker L.G.; RT "The phenotype of a germline mutation in PIGA: the gene somatically mutated RT in paroxysmal nocturnal hemoglobinuria."; RL Am. J. Hum. Genet. 90:295-300(2012). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21 AND SER-24, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP VARIANT PNH1 PHE-155. RX PubMed=8306954; DOI=10.1002/j.1460-2075.1994.tb06240.x; RA Bessler M., Mason P.J., Hilmen P., Miyata T., Yamada N., Takeda J., RA Luzzato L., Kinoshita T.; RT "Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations RT in the PIG-A gene."; RL EMBO J. 13:110-117(1994). RN [15] RP VARIANT PNH1 ASP-297. RX PubMed=8167330; RA Ware R.E., Rosse W.F., Howard T.A.; RT "Mutations within the Piga gene in patients with paroxysmal nocturnal RT hemoglobinuria."; RL Blood 83:2418-2422(1994). RN [16] RP VARIANTS PNH1 TRP-19; HIS-40; ALA-48; ASP-48; ARG-128 AND ARG-239. RX PubMed=10087994; DOI=10.1006/bcmd.1998.0203; RA Nafa K., Bessler M., Castro-Malaspina H., Jhanwar S., Luzzatto L.; RT "The spectrum of somatic mutations in the PIG-A gene in paroxysmal RT nocturnal hemoglobinuria includes large deletions and small duplications."; RL Blood Cells Mol. Dis. 24:370-384(1998). RN [17] RP VARIANT PNH1 VAL-48. RX PubMed=12037021; DOI=10.1136/jcp.55.6.410; RA Yoon J.H., Cho H.I., Park S.S., Chang Y.H., Kim B.K.; RT "Mutation analysis of the PIG-A gene in Korean patients with paroxysmal RT nocturnal haemoglobinuria."; RL J. Clin. Pathol. 55:410-413(2002). RN [18] RP VARIANT NEDEPH LEU-344 DEL, AND INVOLVEMENT IN NEDEPH. RX PubMed=24259288; DOI=10.1002/ajmg.a.36189; RA Swoboda K.J., Margraf R.L., Carey J.C., Zhou H., Newcomb T.M., Coonrod E., RA Durtschi J., Mallempati K., Kumanovics A., Katz B.E., Voelkerding K.V., RA Opitz J.M.; RT "A novel germline PIGA mutation in Ferro-Cerebro-Cutaneous syndrome: a RT neurodegenerative X-linked epileptic encephalopathy with systemic iron- RT overload."; RL Am. J. Med. Genet. A 164A:17-28(2014). RN [19] RP VARIANT MCAHS2 LEU-93. RX PubMed=24259184; DOI=10.1002/ajmg.a.36184; RA van der Crabben S.N., Harakalova M., Brilstra E.H., van Berkestijn F.M., RA Hofstede F.C., van Vught A.J., Cuppen E., Kloosterman W., RA Ploos van Amstel H.K., van Haaften G., van Haelst M.M.; RT "Expanding the spectrum of phenotypes associated with germline PIGA RT mutations: a child with developmental delay, accelerated linear growth, RT facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS RT abnormalities."; RL Am. J. Med. Genet. A 164A:29-35(2014). RN [20] RP VARIANTS MCAHS2 LEU-77; TRP-119; PHE-206 AND 412-ARG--ARG-484 DEL. RX PubMed=24706016; DOI=10.1212/wnl.0000000000000389; RA Kato M., Saitsu H., Murakami Y., Kikuchi K., Watanabe S., Iai M., Miya K., RA Matsuura R., Takayama R., Ohba C., Nakashima M., Tsurusaki Y., Miyake N., RA Hamano S., Osaka H., Hayasaka K., Kinoshita T., Matsumoto N.; RT "PIGA mutations cause early-onset epileptic encephalopathies and RT distinctive features."; RL Neurology 82:1587-1596(2014). RN [21] RP VARIANT MCAHS2 412-ARG--ARG-484 DEL. RX PubMed=26545172; DOI=10.1002/ajmg.a.37452; RA Fauth C., Steindl K., Toutain A., Farrell S., Witsch-Baumgartner M., RA Karall D., Joset P., Boehm S., Baumer A., Maier O., Zschocke J., RA Weksberg R., Marshall C.R., Rauch A.; RT "A recurrent germline mutation in the PIGA gene causes Simpson-Golabi- RT Behmel syndrome type 2."; RL Am. J. Med. Genet. A 170A:392-402(2016). RN [22] RP VARIANT MCAHS2 SER-355. RX PubMed=26993267; DOI=10.1136/jmedgenet-2015-103263; RA Trump N., McTague A., Brittain H., Papandreou A., Meyer E., Ngoh A., RA Palmer R., Morrogh D., Boustred C., Hurst J.A., Jenkins L., Kurian M.A., RA Scott R.H.; RT "Improving diagnosis and broadening the phenotypes in early-onset seizure RT and severe developmental delay disorders through gene panel analysis."; RL J. Med. Genet. 53:310-317(2016). RN [23] RP VARIANT VAL-135. RX PubMed=27864847; DOI=10.1002/humu.23149; RG Clinical Study Group; RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D., RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S., RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.; RT "Diagnostic targeted resequencing in 349 patients with drug-resistant RT pediatric epilepsies identifies causative mutations in 30 different RT genes."; RL Hum. Mutat. 38:216-225(2017). RN [24] RP VARIANTS NEDEPH GLN-77; LEU-127 AND PRO-344, INVOLVEMENT IN NEDEPH, RP CHARACTERIZATION OF VARIANTS NEDEPH GLN-77; LEU-344 DEL AND PRO-344, AND RP CHARACTERIZATION OF VARIANT MCAHS2 412-ARG--ARG-484 DEL. RX PubMed=34875027; DOI=10.1182/blood.2021013519; RA Muckenthaler L., Marques O., Colucci S., Kunz J., Fabrowski P., Bast T., RA Altamura S., Hoechsmann B., Schrezenmeier H., Langlotz M., RA Richter-Pechanska P., Rausch T., Hofmeister-Mielke N., Gunkel N., RA Hentze M.W., Kulozik A.E., Muckenthaler M.U.; RT "Constitutional PIGA mutations cause a novel subtype of hemochromatosis in RT patients with neurologic dysfunction."; RL Blood 139:1418-1422(2022). CC -!- FUNCTION: Catalytic subunit of the glycosylphosphatidylinositol-N- CC acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the CC transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to CC phosphatidylinositol and participates in the first step of GPI CC biosynthesis. {ECO:0000305|PubMed:16162815}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + UDP-N- CC acetyl-alpha-D-glucosamine = a 6-(N-acetyl-alpha-D-glucosaminyl)-1- CC phosphatidyl-1D-myo-inositol + H(+) + UDP; Xref=Rhea:RHEA:14789, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57265, ChEBI:CHEBI:57705, CC ChEBI:CHEBI:57880, ChEBI:CHEBI:58223; EC=2.4.1.198; CC Evidence={ECO:0000305|PubMed:16162815}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14790; CC Evidence={ECO:0000305|PubMed:16162815}; CC -!- PATHWAY: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor CC biosynthesis. {ECO:0000269|PubMed:16162815}. CC -!- SUBUNIT: Component of the glycosylphosphatidylinositol-N- CC acetylglucosaminyltransferase (GPI-GnT) complex composed at least by CC PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815, CC PubMed:9463366). Interacts with PIGC, PIGH, PIGP, PIGQ and DPM2 CC (PubMed:16162815). Interacts directly with PIGY; this interaction CC regulates glycosylphosphatidylinositol-N-acetylglucosaminyltransferase CC activity (PubMed:16162815). Interacts with PIGQ (PubMed:9463366). CC {ECO:0000269|PubMed:16162815, ECO:0000269|PubMed:9463366}. CC -!- INTERACTION: CC P37287; O94777: DPM2; NbExp=4; IntAct=EBI-26643054, EBI-9097061; CC P37287; Q14442: PIGH; NbExp=5; IntAct=EBI-26643054, EBI-2803676; CC P37287; P57054: PIGP; NbExp=5; IntAct=EBI-26643054, EBI-17630288; CC P37287; Q9BRB3: PIGQ; NbExp=5; IntAct=EBI-26643054, EBI-2339260; CC P37287; Q3MUY2: PIGY; NbExp=6; IntAct=EBI-26643054, EBI-3920125; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass CC membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P37287-1; Sequence=Displayed; CC Name=2; CC IsoId=P37287-2; Sequence=VSP_001802; CC Name=3; CC IsoId=P37287-3; Sequence=VSP_043366, VSP_043367; CC -!- DISEASE: Paroxysmal nocturnal hemoglobinuria 1 (PNH1) [MIM:300818]: A CC disorder characterized by hemolytic anemia with hemoglobinuria, CC thromboses in large vessels, and a deficiency in hematopoiesis. Red CC blood cell breakdown with release of hemoglobin into the urine is CC manifested most prominently by dark-colored urine in the morning. CC {ECO:0000269|PubMed:10087994, ECO:0000269|PubMed:12037021, CC ECO:0000269|PubMed:8167330, ECO:0000269|PubMed:8306954, CC ECO:0000269|PubMed:8500164}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Multiple congenital anomalies-hypotonia-seizures syndrome 2 CC (MCAHS2) [MIM:300868]: An X-linked recessive developmental disorder CC characterized by dysmorphic features, neonatal hypotonia, myoclonic CC seizures, and variable congenital anomalies involving the central CC nervous, cardiac, and urinary systems. Most affected individuals die in CC infancy. {ECO:0000269|PubMed:22305531, ECO:0000269|PubMed:24259184, CC ECO:0000269|PubMed:24259288, ECO:0000269|PubMed:24706016, CC ECO:0000269|PubMed:26545172, ECO:0000269|PubMed:26993267, CC ECO:0000269|PubMed:34875027}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Neurodevelopmental disorder with epilepsy and hemochromatosis CC (NEDEPH) [MIM:301072]: An X-liked recessive disorder characterized by CC severe developmental delay, intellectual disability, early-onset CC epilepsy, and early systemic iron overload resulting in juvenile-onset CC hemochromatosis. Variable additional features may include joint CC contractures, visual or hearing impairment, and skin abnormalities. CC {ECO:0000269|PubMed:24259288, ECO:0000269|PubMed:34875027}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. PIGA deficiency causes disruption of iron homeostasis, due to CC failure to attach GPI anchors to hemojuvelin (HJV), a BMP coreceptor CC that regulates hepcidin (HAMP) expression. HAMP is an essential CC regulator of iron absorption and distribution across tissues. PIGA- CC deficient cells lack hemojuvelin surface expression and show CC significantly lower HAMP mRNA levels compared to control cells. CC {ECO:0000269|PubMed:34875027}. CC -!- SIMILARITY: Belongs to the glycosyltransferase group 1 family. CC Glycosyltransferase 4 subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - GTase; CC Note=Phosphatidylinositol N-acetylglucosaminyltransferase subunit A; CC URL="http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_555"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D11466; BAA02019.1; -; mRNA. DR EMBL; X77725; CAB57276.1; ALT_SEQ; Genomic_DNA. DR EMBL; X77726; CAB57276.1; JOINED; Genomic_DNA. DR EMBL; X77727; CAB57276.1; JOINED; Genomic_DNA. DR EMBL; X77728; CAB57276.1; JOINED; Genomic_DNA. DR EMBL; D28791; BAA05966.1; -; Genomic_DNA. DR EMBL; S74936; AAD14160.1; -; mRNA. DR EMBL; AK303538; BAG64564.1; -; mRNA. DR EMBL; AC095351; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC038236; AAH38236.1; -; mRNA. DR EMBL; S61523; AAD13929.1; -; mRNA. DR CCDS; CCDS14165.1; -. [P37287-1] DR CCDS; CCDS48086.2; -. [P37287-3] DR PIR; A46217; A46217. DR RefSeq; NP_002632.1; NM_002641.3. [P37287-1] DR RefSeq; NP_065206.3; NM_020473.3. [P37287-3] DR RefSeq; XP_016885070.1; XM_017029581.1. DR AlphaFoldDB; P37287; -. DR SMR; P37287; -. DR BioGRID; 111295; 46. DR ComplexPortal; CPX-6502; Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex. DR CORUM; P37287; -. DR IntAct; P37287; 27. DR STRING; 9606.ENSP00000369820; -. DR CAZy; GT4; Glycosyltransferase Family 4. DR GlyCosmos; P37287; 1 site, No reported glycans. DR GlyGen; P37287; 1 site. DR iPTMnet; P37287; -. DR PhosphoSitePlus; P37287; -. DR BioMuta; PIGA; -. DR DMDM; 585696; -. DR EPD; P37287; -. DR jPOST; P37287; -. DR MassIVE; P37287; -. DR MaxQB; P37287; -. DR PaxDb; 9606-ENSP00000369820; -. DR PeptideAtlas; P37287; -. DR ProteomicsDB; 55273; -. [P37287-1] DR ProteomicsDB; 55274; -. [P37287-2] DR ProteomicsDB; 55275; -. [P37287-3] DR Pumba; P37287; -. DR Antibodypedia; 23929; 235 antibodies from 29 providers. DR DNASU; 5277; -. DR Ensembl; ENST00000333590.6; ENSP00000369820.3; ENSG00000165195.16. [P37287-1] DR Ensembl; ENST00000482148.6; ENSP00000489528.1; ENSG00000165195.16. [P37287-2] DR Ensembl; ENST00000542278.6; ENSP00000442653.2; ENSG00000165195.16. [P37287-1] DR Ensembl; ENST00000634582.1; ENSP00000489540.1; ENSG00000165195.16. [P37287-3] DR GeneID; 5277; -. DR KEGG; hsa:5277; -. DR MANE-Select; ENST00000333590.6; ENSP00000369820.3; NM_002641.4; NP_002632.1. DR UCSC; uc004cwr.4; human. [P37287-1] DR AGR; HGNC:8957; -. DR CTD; 5277; -. DR DisGeNET; 5277; -. DR GeneCards; PIGA; -. DR HGNC; HGNC:8957; PIGA. DR HPA; ENSG00000165195; Low tissue specificity. DR MalaCards; PIGA; -. DR MIM; 300818; phenotype. DR MIM; 300868; phenotype. DR MIM; 301072; phenotype. DR MIM; 311770; gene. DR neXtProt; NX_P37287; -. DR OpenTargets; ENSG00000165195; -. DR Orphanet; 397922; Ferro-cerebro-cutaneous syndrome. DR Orphanet; 3451; Infantile spasms syndrome. DR Orphanet; 293181; Malignant migrating focal seizures of infancy. DR Orphanet; 300496; Multiple congenital anomalies-hypotonia-seizures syndrome type 2. DR Orphanet; 447; Paroxysmal nocturnal hemoglobinuria. DR PharmGKB; PA33288; -. DR VEuPathDB; HostDB:ENSG00000165195; -. DR eggNOG; KOG1111; Eukaryota. DR GeneTree; ENSGT00390000014405; -. DR HOGENOM; CLU_009583_19_3_1; -. DR InParanoid; P37287; -. DR OMA; QCVLPTM; -. DR OrthoDB; 24420at2759; -. DR PhylomeDB; P37287; -. DR TreeFam; TF105675; -. DR PathwayCommons; P37287; -. DR Reactome; R-HSA-162710; Synthesis of glycosylphosphatidylinositol (GPI). DR SignaLink; P37287; -. DR UniPathway; UPA00196; -. DR BioGRID-ORCS; 5277; 19 hits in 781 CRISPR screens. DR GeneWiki; PIGA; -. DR GenomeRNAi; 5277; -. DR Pharos; P37287; Tbio. DR PRO; PR:P37287; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; P37287; Protein. DR Bgee; ENSG00000165195; Expressed in secondary oocyte and 179 other cell types or tissues. DR ExpressionAtlas; P37287; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:HGNC-UCL. DR GO; GO:0000506; C:glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex; IDA:HGNC-UCL. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0017176; F:phosphatidylinositol N-acetylglucosaminyltransferase activity; IBA:GO_Central. DR GO; GO:0008194; F:UDP-glycosyltransferase activity; TAS:Reactome. DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl. DR GO; GO:0006506; P:GPI anchor biosynthetic process; IBA:GO_Central. DR GO; GO:0016254; P:preassembly of GPI anchor in ER membrane; TAS:Reactome. DR CDD; cd03796; GT4_PIG-A-like; 1. DR Gene3D; 3.40.50.2000; Glycogen Phosphorylase B; 2. DR InterPro; IPR001296; Glyco_trans_1. DR InterPro; IPR039507; PIG-A/GPI3. DR InterPro; IPR013234; PIGA_GPI_anchor_biosynthesis. DR PANTHER; PTHR45871; N-ACETYLGLUCOSAMINYL-PHOSPHATIDYLINOSITOL BIOSYNTHETIC PROTEIN; 1. DR PANTHER; PTHR45871:SF3; PHOSPHATIDYLINOSITOL N-ACETYLGLUCOSAMINYLTRANSFERASE SUBUNIT A; 1. DR Pfam; PF00534; Glycos_transf_1; 1. DR Pfam; PF08288; PIGA; 1. DR SUPFAM; SSF53756; UDP-Glycosyltransferase/glycogen phosphorylase; 1. DR Genevisible; P37287; HS. PE 1: Evidence at protein level; KW Alternative splicing; Disease variant; Endoplasmic reticulum; Epilepsy; KW Glycoprotein; Glycosyltransferase; GPI-anchor biosynthesis; KW Intellectual disability; Lipid metabolism; Membrane; Phosphoprotein; KW Reference proteome; Transferase; Transmembrane; Transmembrane helix. FT CHAIN 1..484 FT /note="Phosphatidylinositol N-acetylglucosaminyltransferase FT subunit A" FT /id="PRO_0000080326" FT TOPO_DOM 1..421 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 422..442 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 443..484 FT /note="Lumenal" FT /evidence="ECO:0000305" FT MOD_RES 21 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:23186163" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CARBOHYD 467 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT VAR_SEQ 1..4 FT /note="MACR -> MELT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_043366" FT VAR_SEQ 5..238 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_043367" FT VAR_SEQ 115..283 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8081230" FT /id="VSP_001802" FT VARIANT 19 FT /note="R -> W (in PNH1; dbSNP:rs34422225)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015442" FT VARIANT 40 FT /note="D -> H (in PNH1)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015436" FT VARIANT 48 FT /note="G -> A (in PNH1)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015437" FT VARIANT 48 FT /note="G -> D (in PNH1)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015438" FT VARIANT 48 FT /note="G -> V (in PNH1)" FT /evidence="ECO:0000269|PubMed:12037021" FT /id="VAR_015439" FT VARIANT 77 FT /note="R -> L (in MCAHS2; dbSNP:rs587777398)" FT /evidence="ECO:0000269|PubMed:24706016" FT /id="VAR_071069" FT VARIANT 77 FT /note="R -> Q (in NEDEPH; does not fully rescue defective FT HAMP expression in PIGA-deficient cells overexpressing HJV, FT suggesting decreased function in GPI anchor biosynthesis FT and absent or reduced HJV anchorage at the cell membrane)" FT /evidence="ECO:0000269|PubMed:34875027" FT /id="VAR_087043" FT VARIANT 93 FT /note="P -> L (in MCAHS2; dbSNP:rs587777400)" FT /evidence="ECO:0000269|PubMed:24259184" FT /id="VAR_071070" FT VARIANT 119 FT /note="R -> W (in MCAHS2; dbSNP:rs587777396)" FT /evidence="ECO:0000269|PubMed:24706016" FT /id="VAR_071071" FT VARIANT 127 FT /note="S -> L (in NEDEPH; uncertain significance)" FT /evidence="ECO:0000269|PubMed:34875027" FT /id="VAR_087044" FT VARIANT 128 FT /note="H -> R (in PNH1)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015440" FT VARIANT 135 FT /note="A -> V (found in a patient with infantile onset FT epileptic encephalopathy with dyskinesia and microcephaly; FT likely pathogenic)" FT /evidence="ECO:0000269|PubMed:27864847" FT /id="VAR_078230" FT VARIANT 155 FT /note="S -> F (in PNH1)" FT /evidence="ECO:0000269|PubMed:8306954" FT /id="VAR_005531" FT VARIANT 206 FT /note="I -> F (in MCAHS2; dbSNP:rs201119959)" FT /evidence="ECO:0000269|PubMed:24706016" FT /id="VAR_071072" FT VARIANT 239 FT /note="G -> R (in PNH1)" FT /evidence="ECO:0000269|PubMed:10087994" FT /id="VAR_015441" FT VARIANT 297 FT /note="N -> D (in PNH1)" FT /evidence="ECO:0000269|PubMed:8167330" FT /id="VAR_005532" FT VARIANT 344 FT /note="L -> P (in NEDEPH; does not fully rescue defective FT HAMP expression in PIGA-deficient cells overexpressing HJV, FT suggesting decreased function in GPI anchor biosynthesis FT and absent or reduced HJV anchorage at the cell membrane)" FT /evidence="ECO:0000269|PubMed:34875027" FT /id="VAR_087045" FT VARIANT 344 FT /note="Missing (in NEDEPH; does not rescue defective HAMP FT expression in PIGA-deficient cells overexpressing HJV, FT suggesting decreased function in GPI anchor biosynthesis FT and absent or reduced HJV anchorage at the cell membrane)" FT /evidence="ECO:0000269|PubMed:24259288, FT ECO:0000269|PubMed:34875027" FT /id="VAR_071073" FT VARIANT 355 FT /note="L -> S (in MCAHS2; uncertain significance)" FT /evidence="ECO:0000269|PubMed:26993267" FT /id="VAR_078721" FT VARIANT 412..484 FT /note="Missing (in MCAHS2; decreased function in GPI anchor FT biosynthesis; does not fully restore GPI-anchored CD59 FT surface expression when transfected in PIGA-null cells; FT does not rescue defective HAMP expression in PIGA-deficient FT cells overexpressing HJV, suggesting absent or reduced HJV FT anchorage at the cell membrane)" FT /evidence="ECO:0000269|PubMed:22305531, FT ECO:0000269|PubMed:24706016, ECO:0000269|PubMed:26545172, FT ECO:0000269|PubMed:34875027" FT /id="VAR_087046" SQ SEQUENCE 484 AA; 54127 MW; 34DCD074A3920852 CRC64; MACRGGAGNG HRASATLSRV SPGSLYTCRT RTHNICMVSD FFYPNMGGVE SHIYQLSQCL IERGHKVIIV THAYGNRKGI RYLTSGLKVY YLPLKVMYNQ STATTLFHSL PLLRYIFVRE RVTIIHSHSS FSAMAHDALF HAKTMGLQTV FTDHSLFGFA DVSSVLTNKL LTVSLCDTNH IICVSYTSKE NTVLRAALNP EIVSVIPNAV DPTDFTPDPF RRHDSITIVV VSRLVYRKGI DLLSGIIPEL CQKYPDLNFI IGGEGPKRII LEEVRERYQL HDRVRLLGAL EHKDVRNVLV QGHIFLNTSL TEAFCMAIVE AASCGLQVVS TRVGGIPEVL PENLIILCEP SVKSLCEGLE KAIFQLKSGT LPAPENIHNI VKTFYTWRNV AERTEKVYDR VSVEAVLPMD KRLDRLISHC GPVTGYIFAL LAVFNFLFLI FLRWMTPDSI IDVAIDATGP RGAWTNNYSH SKRGGENNEI SETR //