ID   ORML3_HUMAN             Reviewed;         153 AA.
AC   Q8N138; B3KS83; Q6UY83;
DT   08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2002, sequence version 1.
DT   07-APR-2021, entry version 148.
DE   RecName: Full=ORM1-like protein 3;
GN   Name=ORMDL3;
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), SUBCELLULAR LOCATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=12093374; DOI=10.1186/gb-2002-3-6-research0027;
RA   Hjelmqvist L., Tuson M., Marfany G., Herrero E., Balcells S.,
RA   Gonzalez-Duarte R.;
RT   "ORMDL proteins are a conserved new family of endoplasmic reticulum
RT   membrane proteins.";
RL   Genome Biol. 3:RESEARCH0027.1-RESEARCH0027.13(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Luoh S.-W., Venkatesan N., Slamon D.J.;
RT   "An evolutionarily conserved gene from the HER-2/Neu amplicon defines a
RT   novel gene family.";
RL   Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA   Li H., Yu R., Shen C., Zhou G., Ke R., Lin L., Yang S.;
RL   Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Placenta, and Testis;
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain, and Colon;
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   [7]
RP   ASSOCIATION OF ORMDL3 EXPRESSION LEVELS WITH SUSCEPTIBILITY TO ASTHMA.
RX   PubMed=17611496; DOI=10.1038/nature06014;
RA   Moffatt M.F., Kabesch M., Liang L., Dixon A.L., Strachan D., Heath S.,
RA   Depner M., von Berg A., Bufe A., Rietschel E., Heinzmann A., Simma B.,
RA   Frischer T., Willis-Owen S.A., Wong K.C., Illig T., Vogelberg C.,
RA   Weiland S.K., von Mutius E., Abecasis G.R., Farrall M., Gut I.G.,
RA   Lathrop G.M., Cookson W.O.;
RT   "Genetic variants regulating ORMDL3 expression contribute to the risk of
RT   childhood asthma.";
RL   Nature 448:470-473(2007).
RN   [8]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO ASTHMA.
RX   PubMed=18395550; DOI=10.1016/j.jaci.2008.01.015;
RA   Tavendale R., Macgregor D.F., Mukhopadhyay S., Palmer C.N.;
RT   "A polymorphism controlling ORMDL3 expression is associated with asthma
RT   that is poorly controlled by current medications.";
RL   J. Allergy Clin. Immunol. 121:860-863(2008).
RN   [9]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO ASTHMA.
RX   PubMed=18760456; DOI=10.1016/j.jaci.2008.06.041;
RA   Sleiman P.M., Annaiah K., Imielinski M., Bradfield J.P., Kim C.E.,
RA   Frackelton E.C., Glessner J.T., Eckert A.W., Otieno F.G., Santa E.,
RA   Thomas K., Smith R.M., Glaberson W., Garris M., Gunnlaugsson S.,
RA   Chiavacci R.M., Allen J., Spergel J., Grundmeier R., Grunstein M.M.,
RA   Magnusson M., Bisgaard H., Grant S.F., Hakonarson H.;
RT   "ORMDL3 variants associated with asthma susceptibility in North Americans
RT   of European ancestry.";
RL   J. Allergy Clin. Immunol. 122:1225-1227(2008).
RN   [10]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO ASTHMA.
RX   PubMed=19133921; DOI=10.1111/j.1398-9995.2008.01912.x;
RA   Wu H., Romieu I., Sienra-Monge J.J., Li H., del Rio-Navarro B.E.,
RA   London S.J.;
RT   "Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and
RT   childhood asthma.";
RL   Allergy 64:629-635(2009).
RN   [11]
RP   POSSIBLE FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY.
RX   PubMed=19819884; DOI=10.1093/hmg/ddp471;
RA   Cantero-Recasens G., Fandos C., Rubio-Moscardo F., Valverde M.A.,
RA   Vicente R.;
RT   "The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-
RT   mediated calcium signaling and cellular stress.";
RL   Hum. Mol. Genet. 19:111-121(2010).
RN   [12]
RP   FUNCTION, AND INTERACTION WITH SPTLC1.
RX   PubMed=20182505; DOI=10.1038/nature08787;
RA   Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K.,
RA   Shevchenko A., Ejsing C.S., Weissman J.S.;
RT   "Orm family proteins mediate sphingolipid homeostasis.";
RL   Nature 463:1048-1053(2010).
CC   -!- FUNCTION: Negative regulator of sphingolipid synthesis. May indirectly
CC       regulate endoplasmic reticulum-mediated Ca(+2) signaling.
CC       {ECO:0000269|PubMed:20182505}.
CC   -!- SUBUNIT: Interacts with SPTLC1. {ECO:0000269|PubMed:20182505}.
CC   -!- INTERACTION:
CC       Q8N138; Q13520: AQP6; NbExp=3; IntAct=EBI-721750, EBI-13059134;
CC       Q8N138; Q3SXY8: ARL13B; NbExp=3; IntAct=EBI-721750, EBI-11343438;
CC       Q8N138; Q8IYJ2-2: C10orf67; NbExp=3; IntAct=EBI-721750, EBI-13381098;
CC       Q8N138; Q8IU89: CERS3; NbExp=3; IntAct=EBI-721750, EBI-18202821;
CC       Q8N138; Q8NI60: COQ8A; NbExp=3; IntAct=EBI-721750, EBI-745535;
CC       Q8N138; Q15125: EBP; NbExp=3; IntAct=EBI-721750, EBI-3915253;
CC       Q8N138; Q9GZR5: ELOVL4; NbExp=3; IntAct=EBI-721750, EBI-18535450;
CC       Q8N138; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-721750, EBI-781551;
CC       Q8N138; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-721750, EBI-18304435;
CC       Q8N138; O00258: GET1; NbExp=3; IntAct=EBI-721750, EBI-18908258;
CC       Q8N138; Q96P66: GPR101; NbExp=3; IntAct=EBI-721750, EBI-17935713;
CC       Q8N138; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-721750, EBI-13345167;
CC       Q8N138; Q7Z5P4: HSD17B13; NbExp=3; IntAct=EBI-721750, EBI-18053395;
CC       Q8N138; O95279: KCNK5; NbExp=3; IntAct=EBI-721750, EBI-3934936;
CC       Q8N138; O95214: LEPROTL1; NbExp=3; IntAct=EBI-721750, EBI-750776;
CC       Q8N138; Q9H2K0: MTIF3; NbExp=3; IntAct=EBI-721750, EBI-3923617;
CC       Q8N138; Q9BRK0: REEP2; NbExp=3; IntAct=EBI-721750, EBI-11337973;
CC       Q8N138; Q86VR2: RETREG3; NbExp=3; IntAct=EBI-721750, EBI-10192441;
CC       Q8N138; Q99942: RNF5; NbExp=3; IntAct=EBI-721750, EBI-348482;
CC       Q8N138; Q03395: ROM1; NbExp=3; IntAct=EBI-721750, EBI-9395257;
CC       Q8N138; Q14973: SLC10A1; NbExp=3; IntAct=EBI-721750, EBI-3923031;
CC       Q8N138; Q9NQQ7-3: SLC35C2; NbExp=3; IntAct=EBI-721750, EBI-17295964;
CC       Q8N138; P30825: SLC7A1; NbExp=3; IntAct=EBI-721750, EBI-4289564;
CC       Q8N138; O15269: SPTLC1; NbExp=2; IntAct=EBI-721750, EBI-1044323;
CC       Q8N138; Q8N9I0: SYT2; NbExp=3; IntAct=EBI-721750, EBI-8032987;
CC       Q8N138; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-721750, EBI-10982110;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:12093374, ECO:0000269|PubMed:19819884}; Multi-pass
CC       membrane protein {ECO:0000269|PubMed:12093374,
CC       ECO:0000269|PubMed:19819884}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q8N138-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q8N138-4; Sequence=VSP_016052;
CC   -!- TISSUE SPECIFICITY: Widely expressed. Expressed in adult and fetal
CC       heart, brain, lung, liver, skeletal muscle and kidney. Expressed in
CC       adult pancreas and placenta and in fetal spleen abd thymus.
CC       {ECO:0000269|PubMed:12093374}.
CC   -!- DISEASE: Asthma (ASTHMA) [MIM:600807]: The most common chronic disease
CC       affecting children and young adults. It is a complex genetic disorder
CC       with a heterogeneous phenotype, largely attributed to the interactions
CC       among many genes and between these genes and the environment. It is
CC       characterized by recurrent attacks of paroxysmal dyspnea, with wheezing
CC       due to spasmodic contraction of the bronchi.
CC       {ECO:0000269|PubMed:18395550, ECO:0000269|PubMed:18760456,
CC       ECO:0000269|PubMed:19133921}. Note=Disease susceptibility is associated
CC       with variants affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: SNPs on 17q21 locus that are associated with childhood
CC       asthma also show a consistent and strong association with transcript
CC       levels of ORMDL3, indicating that genetic variants regulating ORMDL3
CC       expression are determinants of susceptibility to childhood asthma.
CC   -!- SIMILARITY: Belongs to the ORM family. {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; AF395708; AAM43507.1; -; mRNA.
DR   EMBL; AF373101; AAN76521.1; -; mRNA.
DR   EMBL; AF373102; AAN76522.1; -; mRNA.
DR   EMBL; AK074811; BAC11223.1; -; mRNA.
DR   EMBL; AY357943; AAQ57273.1; -; mRNA.
DR   EMBL; AK075212; BAC11476.1; -; mRNA.
DR   EMBL; AK093063; BAG52645.1; -; mRNA.
DR   EMBL; CH471152; EAW60617.1; -; Genomic_DNA.
DR   EMBL; BC017087; AAH17087.1; -; mRNA.
DR   EMBL; BC071833; AAH71833.1; -; mRNA.
DR   CCDS; CCDS11355.1; -. [Q8N138-1]
DR   RefSeq; NP_001307730.1; NM_001320801.1. [Q8N138-1]
DR   RefSeq; NP_001307731.1; NM_001320802.1. [Q8N138-1]
DR   RefSeq; NP_001307732.1; NM_001320803.1. [Q8N138-1]
DR   RefSeq; NP_644809.1; NM_139280.3. [Q8N138-1]
DR   RefSeq; XP_016880835.1; XM_017025346.1.
DR   RefSeq; XP_016880836.1; XM_017025347.1.
DR   RefSeq; XP_016880837.1; XM_017025348.1.
DR   BioGRID; 125114; 43.
DR   CORUM; Q8N138; -.
DR   DIP; DIP-48687N; -.
DR   IntAct; Q8N138; 32.
DR   STRING; 9606.ENSP00000377724; -.
DR   iPTMnet; Q8N138; -.
DR   PhosphoSitePlus; Q8N138; -.
DR   BioMuta; ORMDL3; -.
DR   DMDM; 74728486; -.
DR   EPD; Q8N138; -.
DR   jPOST; Q8N138; -.
DR   MassIVE; Q8N138; -.
DR   MaxQB; Q8N138; -.
DR   PaxDb; Q8N138; -.
DR   PeptideAtlas; Q8N138; -.
DR   PRIDE; Q8N138; -.
DR   ProteomicsDB; 71543; -. [Q8N138-1]
DR   ProteomicsDB; 71544; -. [Q8N138-4]
DR   TopDownProteomics; Q8N138-1; -. [Q8N138-1]
DR   Antibodypedia; 54876; 111 antibodies.
DR   DNASU; 94103; -.
DR   Ensembl; ENST00000304046; ENSP00000304858; ENSG00000172057. [Q8N138-1]
DR   Ensembl; ENST00000394169; ENSP00000377724; ENSG00000172057. [Q8N138-1]
DR   Ensembl; ENST00000579695; ENSP00000464693; ENSG00000172057. [Q8N138-1]
DR   Ensembl; ENST00000584220; ENSP00000464455; ENSG00000172057. [Q8N138-4]
DR   GeneID; 94103; -.
DR   KEGG; hsa:94103; -.
DR   UCSC; uc002htj.3; human. [Q8N138-1]
DR   CTD; 94103; -.
DR   DisGeNET; 94103; -.
DR   GeneCards; ORMDL3; -.
DR   HGNC; HGNC:16038; ORMDL3.
DR   HPA; ENSG00000172057; Low tissue specificity.
DR   MIM; 600807; phenotype.
DR   MIM; 610075; gene.
DR   neXtProt; NX_Q8N138; -.
DR   OpenTargets; ENSG00000172057; -.
DR   PharmGKB; PA32821; -.
DR   VEuPathDB; HostDB:ENSG00000172057.9; -.
DR   eggNOG; KOG3319; Eukaryota.
DR   GeneTree; ENSGT00950000183178; -.
DR   HOGENOM; CLU_072117_3_0_1; -.
DR   InParanoid; Q8N138; -.
DR   OMA; CLYTRND; -.
DR   PhylomeDB; Q8N138; -.
DR   TreeFam; TF323369; -.
DR   PathwayCommons; Q8N138; -.
DR   Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   BioGRID-ORCS; 94103; 12 hits in 998 CRISPR screens.
DR   ChiTaRS; ORMDL3; human.
DR   GenomeRNAi; 94103; -.
DR   Pharos; Q8N138; Tbio.
DR   PRO; PR:Q8N138; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; Q8N138; protein.
DR   Bgee; ENSG00000172057; Expressed in liver and 219 other tissues.
DR   ExpressionAtlas; Q8N138; baseline and differential.
DR   Genevisible; Q8N138; HS.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
DR   GO; GO:0035579; C:specific granule membrane; TAS:Reactome.
DR   GO; GO:0035339; C:SPOTS complex; IDA:UniProtKB.
DR   GO; GO:0090156; P:cellular sphingolipid homeostasis; IBA:GO_Central.
DR   GO; GO:0006672; P:ceramide metabolic process; IMP:UniProtKB.
DR   GO; GO:0061744; P:motor behavior; IEA:Ensembl.
DR   GO; GO:0042552; P:myelination; IEA:Ensembl.
DR   GO; GO:0002903; P:negative regulation of B cell apoptotic process; IMP:MGI.
DR   GO; GO:1900060; P:negative regulation of ceramide biosynthetic process; IMP:MGI.
DR   GO; GO:1904221; P:negative regulation of serine C-palmitoyltransferase activity; IEA:Ensembl.
DR   GO; GO:0043312; P:neutrophil degranulation; TAS:Reactome.
DR   GO; GO:0010508; P:positive regulation of autophagy; IDA:MGI.
DR   GO; GO:1900182; P:positive regulation of protein localization to nucleus; IDA:MGI.
DR   GO; GO:0006940; P:regulation of smooth muscle contraction; IEA:Ensembl.
DR   GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl.
DR   InterPro; IPR007203; ORMDL.
DR   InterPro; IPR029883; ORML3.
DR   PANTHER; PTHR12665; PTHR12665; 1.
DR   PANTHER; PTHR12665:SF11; PTHR12665:SF11; 1.
DR   Pfam; PF04061; ORMDL; 1.
DR   PIRSF; PIRSF018147; ORMDL; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Asthma; Endoplasmic reticulum; Membrane;
KW   Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..153
FT                   /note="ORM1-like protein 3"
FT                   /id="PRO_0000215639"
FT   TOPO_DOM        1..21
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        22..42
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        43..94
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        95..117
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        118..153
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         43..58
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.3"
FT                   /id="VSP_016052"
SQ   SEQUENCE   153 AA;  17495 MW;  3EF483CA5C03EC2E CRC64;
     MNVGTAHSEV NPNTRVMNSR GIWLSYVLAI GLLHIVLLSI PFVSVPVVWT LTNLIHNMGM
     YIFLHTVKGT PFETPDQGKA RLLTHWEQMD YGVQFTASRK FLTITPIVLY FLTSFYTKYD
     QIHFVLNTVS LMSVLIPKLP QLHGVRIFGI NKY
//