ID PHEX_HUMAN Reviewed; 749 AA. AC P78562; O00678; Q13646; Q2M325; Q93032; Q99827; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 24-JAN-2024, entry version 205. DE RecName: Full=Phosphate-regulating neutral endopeptidase PHEX; DE EC=3.4.24.- {ECO:0000269|PubMed:18597632, ECO:0000269|PubMed:9593714}; DE AltName: Full=Metalloendopeptidase homolog PEX; DE AltName: Full=Vitamin D-resistant hypophosphatemic rickets protein; DE AltName: Full=X-linked hypophosphatemia protein; DE Short=HYP; GN Name=PHEX; Synonyms=PEX; 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 [GENOMIC DNA], AND VARIANTS XLHR ARG-85; LEU-534; RP ARG-579 AND PRO-651. RX PubMed=9199930; DOI=10.1101/gr.7.6.573; RA Francis F., Strom T.M., Hennig S., Boeddrich A., Lorenz B., Brandau O., RA Mohnike K.L., Cagnoli M., Steffens C., Klages S., Borzym K., Pohl T., RA Oudet C.L., Econs M.J., Rowe P.S.N., Reinhardt R., Meitinger T., RA Lehrach H.; RT "Genomic organization of the human PEX gene mutated in X-linked dominant RT hypophosphatemic rickets."; RL Genome Res. 7:573-585(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE. RX PubMed=9077527; DOI=10.1172/jci119276; RA Beck L., Soumounou Y., Martel J., Krishnamurthy G., Gauthier C., RA Goodyer C.G., Tenenhouse H.S.; RT "Pex/PEX tissue distribution and evidence for a deletion in the 3' region RT of the Pex gene in X-linked hypophosphatemic mice."; RL J. Clin. Invest. 99:1200-1209(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Bone; RX PubMed=9199999; DOI=10.1359/jbmr.1997.12.7.1009; RA Guo R., Quarles L.D.; RT "Cloning and sequencing of human PEX from a bone cDNA library: evidence for RT its developmental stage-specific regulation in osteoblasts."; RL J. Bone Miner. Res. 12:1009-1017(1997). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=9070861; DOI=10.1006/bbrc.1997.6153; RA Grieff M., Mumm S., Waeltz P., Mazzarella R., Whyte M.P., Thakker R.V., RA Schlessinger D.; RT "Expression and cloning of the human X-linked hypophosphatemia gene cDNA."; RL Biochem. Biophys. Res. Commun. 231:635-639(1997). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND TOPOLOGY. RX PubMed=9593714; DOI=10.1074/jbc.273.22.13729; RA Lipman M.L., Panda D., Bennett H.P., Henderson J.E., Shane E., Shen Y., RA Goltzman D., Karaplis A.C.; RT "Cloning of human PEX cDNA. Expression, subcellular localization, and RT endopeptidase activity."; RL J. Biol. Chem. 273:13729-13737(1998). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS XLHR TYR-85; CYS-166; RP SER-252; ILE-253 AND VAL-579. RX PubMed=9106524; RA Holm I.A., Huang X., Kunkel L.M.; RT "Mutational analysis of the PEX gene in patients with X-linked RT hypophosphatemic rickets."; RL Am. J. Hum. Genet. 60:790-797(1997). RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-641. RX PubMed=7550339; DOI=10.1038/ng1095-130; RG The HYP consortium; RA Francis F., Hennig S., Korn B., Reinhardt R., de Jong P., Poustka A., RA Lehrach H., Rowe P.S.N., Goulding J.N., Summerfield T., Mountford R., RA Read A.P., Popowska E., Pronicka E., Davies K.E., Oriordan J.L.H., RA Econs M.J., Nesbitt T., Drezner M.K., Oudet C.L., Pannetier S., Hanauer A., RA Strom T.M., Meindl A., Lorenz B., Cagnoli M., Mohnike K.L., Murken J., RA Meitinger T.; RT "A gene (PEX) with homologies to endopeptidases is mutated in patients with RT X-linked hypophosphatemic rickets."; RL Nat. Genet. 11:130-136(1995). RN [10] RP FUNCTION. RX PubMed=12220505; DOI=10.1016/s0006-291x(02)02125-3; RA Guo R., Rowe P.S., Liu S., Simpson L.G., Xiao Z.S., Quarles L.D.; RT "Inhibition of MEPE cleavage by Phex."; RL Biochem. Biophys. Res. Commun. 297:38-45(2002). RN [11] RP COFACTOR, AND INTERACTION WITH MEPE. RX PubMed=15664000; DOI=10.1016/j.bone.2004.09.015; RA Rowe P.S., Garrett I.R., Schwarz P.M., Carnes D.L., Lafer E.M., Mundy G.R., RA Gutierrez G.E.; RT "Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the RT MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets RT (HYP)."; RL Bone 36:33-46(2005). RN [12] RP FUNCTION, AND INTERACTION WITH MEPE. RX PubMed=18162525; DOI=10.1210/en.2007-1205; RA Martin A., David V., Laurence J.S., Schwarz P.M., Lafer E.M., Hedge A.M., RA Rowe P.S.; RT "Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides RT (minhibins): ASARM-peptide(s) are directly responsible for defective RT mineralization in HYP."; RL Endocrinology 149:1757-1772(2008). RN [13] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=18597632; DOI=10.1359/jbmr.080601; RA Addison W.N., Nakano Y., Loisel T., Crine P., McKee M.D.; RT "MEPE-ASARM peptides control extracellular matrix mineralization by binding RT to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM."; RL J. Bone Miner. Res. 23:1638-1649(2008). RN [14] RP VARIANTS XLHR SER-77; PRO-138; LEU-534 AND ARG-579. RX PubMed=9097956; DOI=10.1093/hmg/6.4.539; RA Rowe P.S.N., Oudet C.L., Francis F., Sinding C., Pannetier S., Econs M.J., RA Strom T.M., Meitinger T., Garabedian M., David A., Macher M.-A., RA Questiaux E., Popowska E., Pronicka E., Read A.P., Mokrzycki A., RA Glorieux F.H., Drezner M.K., Hanauer A., Lehrach H., Goulding J.N., RA O'Riordan J.L.H.; RT "Distribution of mutations in the PEX gene in families with X-linked RT hypophosphataemic rickets (HYP)."; RL Hum. Mol. Genet. 6:539-549(1997). RN [15] RP VARIANT XLHR PRO-555. RX PubMed=9768646; DOI=10.1210/jcem.83.10.5167; RA Econs M.J., Friedman N.E., Rowe P.S.N., Speer M.C., Francis F., Strom T.M., RA Oudet C.L., Smith J.A., Ninomiya J.T., Lee B.E., Bergen H.; RT "A PHEX gene mutation is responsible for adult-onset vitamin D-resistant RT hypophosphatemic osteomalacia: evidence that the disorder is not a distinct RT entity from X-linked hypophosphatemic rickets."; RL J. Clin. Endocrinol. Metab. 83:3459-3462(1998). RN [16] RP VARIANTS XLHR PHE-317; LEU-534; ARG-579; ARG-621; ASN-680 DEL; THR-720; RP TYR-731 AND ARG-749. RX PubMed=9768674; DOI=10.1210/jcem.83.10.5180; RA Dixon P.H., Christie P.T., Wooding C., Trump D., Grieff M., Holm I.A., RA Gertner J.M., Schmidtke J., Shah B., Shaw N., Smith C., Tau C., RA Schlessinger D., Whyte M.P., Thakker R.V.; RT "Mutational analysis of PHEX gene in X-linked hypophosphatemia."; RL J. Clin. Endocrinol. Metab. 83:3615-3623(1998). RN [17] RP VARIANTS XLHR SER-80; PHE-142; GLY-237; CYS-530; ASP-573; SER-733 AND RP TRP-746. RX PubMed=10439971; DOI=10.1038/sj.ejhg.5200341; RA Filisetti D., Ostermann G., von Bredow M., Strom T.M., Filler G., RA Ehrich J., Pannetier S., Garnier J.-M., Rowe P.S.N., Francis F., RA Julienne A., Hanauer A., Econs M.J., Oudet C.L.; RT "Non-random distribution of mutations in the PHEX gene, and under-detected RT missense mutations at non-conserved residues."; RL Eur. J. Hum. Genet. 7:615-619(1999). RN [18] RP VARIANTS XLHR PHE-85; PRO-141; VAL-341 DEL; PRO-567; LYS-680 AND TYR-693. RX PubMed=10737991; RX DOI=10.1002/(sici)1098-1004(200004)15:4<383::aid-humu18>3.0.co;2-#; RA Tyynismaa H., Kaitila I., Naentoe-Salonen K., Ala-Houhala M., Alitalo T.; RT "Identification of fifteen novel PHEX gene mutations in Finnish patients RT with hypophosphatemic rickets."; RL Hum. Mutat. 15:383-384(2000). RN [19] RP VARIANTS XLHR ARG-160 AND ASN-444 INS. RX PubMed=11004247; DOI=10.1203/00006450-200010000-00019; RA Sato K., Tajima T., Nakae J., Adachi M., Asakura Y., Tachibana K., Suwa S., RA Katsumata N., Tanaka T., Hayashi Y., Abe S., Murashita M., Okuhara K., RA Shinohara N., Fujieda K.; RT "Three novel PHEX gene mutations in Japanese patients with X-linked RT hypophosphatemic rickets."; RL Pediatr. Res. 48:536-540(2000). CC -!- FUNCTION: Peptidase that cleaves SIBLING (small integrin-binding CC ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating CC their biological activity (PubMed:9593714, PubMed:15664000, CC PubMed:18162525, PubMed:18597632). Cleaves ASARM peptides between Ser CC and Glu or Asp residues (PubMed:18597632). Regulates osteogenic cell CC differentiation and bone mineralization through the cleavage of the CC MEPE-derived ASARM peptide (PubMed:18597632). Promotes dentin CC mineralization and renal phosphate reabsorption by cleaving DMP1- and CC MEPE-derived ASARM peptides (PubMed:18597632, PubMed:18162525). CC Inhibits the cleavage of MEPE by CTSB/cathepsin B thus preventing MEPE CC degradation (PubMed:12220505). {ECO:0000250|UniProtKB:P70669, CC ECO:0000269|PubMed:12220505, ECO:0000269|PubMed:18162525, CC ECO:0000269|PubMed:18597632}. CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:15664000}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:15664000}; CC -!- SUBUNIT: Interacts with MEPE; the interaction is zinc-dependent (via CC ASARM motif). {ECO:0000269|PubMed:15664000, CC ECO:0000269|PubMed:18162525}. CC -!- INTERACTION: CC P78562; Q9NQ76: MEPE; NbExp=2; IntAct=EBI-2827676, EBI-1753293; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9593714}; CC Single-pass type II membrane protein {ECO:0000269|PubMed:9593714}. CC -!- TISSUE SPECIFICITY: Specifically expressed in ovary (PubMed:9070861). CC Expressed at low levels in kidney (PubMed:9070861). CC {ECO:0000269|PubMed:9070861}. CC -!- DEVELOPMENTAL STAGE: Expressed in fetal lung (PubMed:9070861, CC PubMed:9077527). Expressed in fetal calvaria and to a lesser extent in CC fetal kidney and skeletal muscles (PubMed:9593714, PubMed:9077527). CC {ECO:0000269|PubMed:9070861, ECO:0000269|PubMed:9077527, CC ECO:0000269|PubMed:9593714}. CC -!- DISEASE: Hypophosphatemic rickets, X-linked dominant (XLHR) CC [MIM:307800]: A disorder characterized by impaired phosphate uptake in CC the kidney, which is likely to be caused by abnormal regulation of CC sodium phosphate cotransport in the proximal tubules. Clinical CC manifestations include skeletal deformities, growth failure, CC craniosynostosis, paravertebral calcifications, pseudofractures in CC lower extremities, and muscular hypotonia with onset in early CC childhood. X-linked hypophosphatemic rickets is the most common form of CC hypophosphatemia with an incidence of 1 in 20000. CC {ECO:0000269|PubMed:10439971, ECO:0000269|PubMed:10737991, CC ECO:0000269|PubMed:11004247, ECO:0000269|PubMed:9097956, CC ECO:0000269|PubMed:9106524, ECO:0000269|PubMed:9199930, CC ECO:0000269|PubMed:9768646, ECO:0000269|PubMed:9768674}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE- CC ProRule:PRU01233, ECO:0000305}. 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; Y08111; CAA69326.1; -; Genomic_DNA. DR EMBL; Y08112; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08113; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08114; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08115; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08116; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08117; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08118; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08119; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08120; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08121; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08122; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08123; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08124; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08125; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08126; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08127; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08128; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08129; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08130; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08131; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; Y08132; CAA69326.1; JOINED; Genomic_DNA. DR EMBL; U75645; AAB47749.1; -; mRNA. DR EMBL; U87284; AAB47562.1; -; mRNA. DR EMBL; AD000712; AAB51604.1; -; mRNA. DR EMBL; AH004966; AAB42219.1; -; Genomic_DNA. DR EMBL; U82970; AAC24487.1; -; mRNA. DR EMBL; U73024; AAD08630.1; -; Genomic_DNA. DR EMBL; Y10196; CAA71258.1; -; Genomic_DNA. DR EMBL; BC105057; AAI05058.1; -; mRNA. DR EMBL; BC105059; AAI05060.1; -; mRNA. DR EMBL; U60475; AAC50552.1; -; mRNA. DR CCDS; CCDS14204.1; -. DR RefSeq; NP_000435.3; NM_000444.5. DR RefSeq; NP_001269683.1; NM_001282754.1. DR AlphaFoldDB; P78562; -. DR SMR; P78562; -. DR BioGRID; 111270; 3. DR IntAct; P78562; 3. DR STRING; 9606.ENSP00000368682; -. DR MEROPS; M13.091; -. DR GlyCosmos; P78562; 8 sites, No reported glycans. DR GlyGen; P78562; 8 sites. DR iPTMnet; P78562; -. DR PhosphoSitePlus; P78562; -. DR BioMuta; PHEX; -. DR DMDM; 2499917; -. DR EPD; P78562; -. DR jPOST; P78562; -. DR MassIVE; P78562; -. DR PaxDb; 9606-ENSP00000368682; -. DR PeptideAtlas; P78562; -. DR ProteomicsDB; 57655; -. DR Antibodypedia; 24481; 171 antibodies from 26 providers. DR DNASU; 5251; -. DR Ensembl; ENST00000379374.5; ENSP00000368682.4; ENSG00000102174.10. DR GeneID; 5251; -. DR KEGG; hsa:5251; -. DR MANE-Select; ENST00000379374.5; ENSP00000368682.4; NM_000444.6; NP_000435.3. DR UCSC; uc004dah.5; human. DR AGR; HGNC:8918; -. DR CTD; 5251; -. DR DisGeNET; 5251; -. DR GeneCards; PHEX; -. DR GeneReviews; PHEX; -. DR HGNC; HGNC:8918; PHEX. DR HPA; ENSG00000102174; Tissue enhanced (ovary). DR MalaCards; PHEX; -. DR MIM; 300550; gene. DR MIM; 307800; phenotype. DR neXtProt; NX_P78562; -. DR OpenTargets; ENSG00000102174; -. DR Orphanet; 89936; X-linked hypophosphatemia. DR PharmGKB; PA33258; -. DR VEuPathDB; HostDB:ENSG00000102174; -. DR eggNOG; KOG3624; Eukaryota. DR GeneTree; ENSGT00940000157313; -. DR HOGENOM; CLU_006187_4_1_1; -. DR InParanoid; P78562; -. DR OMA; QAKPEYC; -. DR OrthoDB; 202716at2759; -. DR PhylomeDB; P78562; -. DR TreeFam; TF315192; -. DR BRENDA; 3.4.24.B15; 2681. DR PathwayCommons; P78562; -. DR SignaLink; P78562; -. DR BioGRID-ORCS; 5251; 19 hits in 771 CRISPR screens. DR ChiTaRS; PHEX; human. DR GeneWiki; PHEX; -. DR GenomeRNAi; 5251; -. DR Pharos; P78562; Tbio. DR PRO; PR:P78562; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; P78562; Protein. DR Bgee; ENSG00000102174; Expressed in secondary oocyte and 91 other cell types or tissues. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; TAS:ProtInc. DR GO; GO:0060348; P:bone development; IEA:Ensembl. DR GO; GO:0030282; P:bone mineralization; IEA:Ensembl. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IEA:Ensembl. DR GO; GO:0071305; P:cellular response to vitamin D; IEA:Ensembl. DR GO; GO:0030324; P:lung development; IEA:Ensembl. DR GO; GO:0042476; P:odontogenesis; IEA:Ensembl. DR GO; GO:0019637; P:organophosphate metabolic process; IEA:Ensembl. DR GO; GO:0036211; P:protein modification process; TAS:ProtInc. DR GO; GO:0016485; P:protein processing; IBA:GO_Central. DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB. DR GO; GO:0060416; P:response to growth hormone; IEA:Ensembl. DR GO; GO:1990418; P:response to insulin-like growth factor stimulus; IEA:Ensembl. DR GO; GO:1904383; P:response to sodium phosphate; IEA:Ensembl. DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc. DR CDD; cd08662; M13; 1. DR Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1. DR Gene3D; 1.10.1380.10; Neutral endopeptidase , domain2; 1. DR InterPro; IPR024079; MetalloPept_cat_dom_sf. DR InterPro; IPR000718; Peptidase_M13. DR InterPro; IPR018497; Peptidase_M13_C. DR InterPro; IPR042089; Peptidase_M13_dom_2. DR InterPro; IPR008753; Peptidase_M13_N. DR PANTHER; PTHR11733:SF133; PHOSPHATE-REGULATING NEUTRAL ENDOPEPTIDASE PHEX; 1. DR PANTHER; PTHR11733; ZINC METALLOPROTEASE FAMILY M13 NEPRILYSIN-RELATED; 1. DR Pfam; PF01431; Peptidase_M13; 1. DR Pfam; PF05649; Peptidase_M13_N; 1. DR PRINTS; PR00786; NEPRILYSIN. DR SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1. DR PROSITE; PS51885; NEPRILYSIN; 1. DR PROSITE; PS00142; ZINC_PROTEASE; 1. DR Genevisible; P78562; HS. PE 1: Evidence at protein level; KW Biomineralization; Cell membrane; Disease variant; Disulfide bond; KW Glycoprotein; Hydrolase; Membrane; Metal-binding; Metalloprotease; KW Protease; Reference proteome; Signal-anchor; Transmembrane; KW Transmembrane helix; Zinc. FT CHAIN 1..749 FT /note="Phosphate-regulating neutral endopeptidase PHEX" FT /id="PRO_0000078228" FT TOPO_DOM 1..20 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:9593714" FT TRANSMEM 21..41 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000269|PubMed:9593714" FT TOPO_DOM 42..641 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:9593714" FT DOMAIN 53..749 FT /note="Peptidase M13" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT ACT_SITE 581 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233, FT ECO:0000255|PROSITE-ProRule:PRU10095" FT ACT_SITE 646 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT BINDING 580 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233, FT ECO:0000255|PROSITE-ProRule:PRU10095" FT BINDING 584 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233, FT ECO:0000255|PROSITE-ProRule:PRU10095" FT BINDING 642 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT CARBOHYD 71 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 238 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 263 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 290 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 301 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 377 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 484 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 736 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 54..59 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT DISULFID 77..733 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT DISULFID 85..693 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT DISULFID 142..406 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT DISULFID 617..746 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233" FT VARIANT 77 FT /note="C -> S (in XLHR)" FT /evidence="ECO:0000269|PubMed:9097956" FT /id="VAR_006738" FT VARIANT 80 FT /note="F -> S (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010616" FT VARIANT 85 FT /note="C -> F (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010617" FT VARIANT 85 FT /note="C -> R (in XLHR; dbSNP:rs1556014287)" FT /evidence="ECO:0000269|PubMed:9199930" FT /id="VAR_010618" FT VARIANT 85 FT /note="C -> Y (in XLHR; dbSNP:rs137853269)" FT /evidence="ECO:0000269|PubMed:9106524" FT /id="VAR_006739" FT VARIANT 138 FT /note="L -> P (in XLHR)" FT /evidence="ECO:0000269|PubMed:9097956" FT /id="VAR_006740" FT VARIANT 141 FT /note="S -> P (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010619" FT VARIANT 142 FT /note="C -> F (in XLHR)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010620" FT VARIANT 160 FT /note="L -> R (in XLHR)" FT /evidence="ECO:0000269|PubMed:11004247" FT /id="VAR_010621" FT VARIANT 166 FT /note="R -> C (in XLHR; dbSNP:rs751230094)" FT /evidence="ECO:0000269|PubMed:9106524" FT /id="VAR_006741" FT VARIANT 237 FT /note="D -> G (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010622" FT VARIANT 252 FT /note="F -> S (in XLHR; dbSNP:rs267606945)" FT /evidence="ECO:0000269|PubMed:9106524" FT /id="VAR_006742" FT VARIANT 253 FT /note="M -> I (in XLHR; dbSNP:rs267606946)" FT /evidence="ECO:0000269|PubMed:9106524" FT /id="VAR_006743" FT VARIANT 317 FT /note="Y -> F (in XLHR)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010623" FT VARIANT 341 FT /note="Missing (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010624" FT VARIANT 444 FT /note="W -> WN (in XLHR)" FT /evidence="ECO:0000269|PubMed:11004247" FT /id="VAR_010625" FT VARIANT 530 FT /note="W -> C (in XLHR; dbSNP:rs1556091855)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010626" FT VARIANT 534 FT /note="P -> L (in XLHR; dbSNP:rs886041363)" FT /evidence="ECO:0000269|PubMed:9097956, FT ECO:0000269|PubMed:9199930, ECO:0000269|PubMed:9768674" FT /id="VAR_006744" FT VARIANT 555 FT /note="L -> P (in XLHR; dbSNP:rs137853270)" FT /evidence="ECO:0000269|PubMed:9768646" FT /id="VAR_010627" FT VARIANT 567 FT /note="R -> P (in XLHR; sporadic; dbSNP:rs760870713)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010628" FT VARIANT 573 FT /note="A -> D (in XLHR; sporadic; dbSNP:rs1556135308)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010629" FT VARIANT 579 FT /note="G -> R (in XLHR; dbSNP:rs875989883)" FT /evidence="ECO:0000269|PubMed:9097956, FT ECO:0000269|PubMed:9199930, ECO:0000269|PubMed:9768674" FT /id="VAR_006745" FT VARIANT 579 FT /note="G -> V (in XLHR; dbSNP:rs1057517980)" FT /evidence="ECO:0000269|PubMed:9106524" FT /id="VAR_006746" FT VARIANT 621 FT /note="Q -> R (in XLHR)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010630" FT VARIANT 651 FT /note="R -> P (in XLHR; dbSNP:rs748792378)" FT /evidence="ECO:0000269|PubMed:9199930" FT /id="VAR_010631" FT VARIANT 680 FT /note="N -> K (in XLHR; sporadic; dbSNP:rs1556151526)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010633" FT VARIANT 680 FT /note="Missing (in XLHR)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010632" FT VARIANT 693 FT /note="C -> Y (in XLHR; sporadic; dbSNP:rs1556200989)" FT /evidence="ECO:0000269|PubMed:10737991" FT /id="VAR_010634" FT VARIANT 720 FT /note="A -> T (in XLHR)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010635" FT VARIANT 731 FT /note="F -> Y (in XLHR)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010636" FT VARIANT 733 FT /note="C -> S (in XLHR; sporadic; dbSNP:rs1057517981)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010637" FT VARIANT 746 FT /note="C -> W (in XLHR; sporadic)" FT /evidence="ECO:0000269|PubMed:10439971" FT /id="VAR_010638" FT VARIANT 749 FT /note="W -> R (in XLHR; dbSNP:rs1556206403)" FT /evidence="ECO:0000269|PubMed:9768674" FT /id="VAR_010639" FT CONFLICT 363 FT /note="A -> D (in Ref. 9; AAC50552)" FT /evidence="ECO:0000305" FT CONFLICT 403 FT /note="W -> R (in Ref. 9; AAC50552)" FT /evidence="ECO:0000305" FT CONFLICT 641 FT /note="G -> A (in Ref. 9; AAC50552)" FT /evidence="ECO:0000305" SQ SEQUENCE 749 AA; 86474 MW; 7C4F9F3E2471C6A8 CRC64; MEAETGSSVE TGKKANRGTR IALVVFVGGT LVLGTILFLV SQGLLSLQAK QEYCLKPECI EAAAAILSKV NLSVDPCDNF FRFACDGWIS NNPIPEDMPS YGVYPWLRHN VDLKLKELLE KSISRRRDTE AIQKAKILYS SCMNEKAIEK ADAKPLLHIL RHSPFRWPVL ESNIGPEGVW SERKFSLLQT LATFRGQYSN SVFIRLYVSP DDKASNEHIL KLDQATLSLA VREDYLDNST EAKSYRDALY KFMVDTAVLL GANSSRAEHD MKSVLRLEIK IAEIMIPHEN RTSEAMYNKM NISELSAMIP QFDWLGYIKK VIDTRLYPHL KDISPSENVV VRVPQYFKDL FRILGSERKK TIANYLVWRM VYSRIPNLSR RFQYRWLEFS RVIQGTTTLL PQWDKCVNFI ESALPYVVGK MFVDVYFQED KKEMMEELVE GVRWAFIDML EKENEWMDAG TKRKAKEKAR AVLAKVGYPE FIMNDTHVNE DLKAIKFSEA DYFGNVLQTR KYLAQSDFFW LRKAVPKTEW FTNPTTVNAF YSASTNQIRF PAGELQKPFF WGTEYPRSLS YGAIGVIVGH EFTHGFDNNG RKYDKNGNLD PWWSTESEEK FKEKTKCMIN QYSNYYWKKA GLNVKGKRTL GENIADNGGL REAFRAYRKW INDRRQGLEE PLLPGITFTN NQLFFLSYAH VRCNSYRPEA AREQVQIGAH SPPQFRVNGA ISNFEEFQKA FNCPPNSTMN RGMDSCRLW //