ITM2B_HUMAN
ID ITM2B_HUMAN Reviewed; 266 AA.
AC Q9Y287; Q5W0A3; Q96B24; Q9NYH1;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Integral membrane protein 2B;
DE AltName: Full=Immature BRI2;
DE Short=imBRI2;
DE AltName: Full=Protein E25B;
DE AltName: Full=Transmembrane protein BRI;
DE Short=Bri;
DE Contains:
DE RecName: Full=BRI2, membrane form;
DE AltName: Full=Mature BRI2;
DE Short=mBRI2;
DE Contains:
DE RecName: Full=BRI2 intracellular domain;
DE Short=BRI2 ICD;
DE Contains:
DE RecName: Full=BRI2C, soluble form;
DE Contains:
DE RecName: Full=Bri23 peptide;
DE Short=Bri2-23;
DE AltName: Full=ABri23;
DE AltName: Full=C-terminal peptide;
DE AltName: Full=P23 peptide;
GN Name=ITM2B; Synonyms=BRI, BRI2;
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], INVOLVEMENT IN CAA-ITM2B1, AND VARIANT
RP CAA-ITM2B1 ARG-THR-VAL-LYS-LYS-ASN-ILE-ILE-GLU-GLU-ASN-266 INS.
RC TISSUE=Pituitary;
RX PubMed=10391242; DOI=10.1038/21637;
RA Vidal R., Frangione B., Rostagno A., Mead S., Revesz T., Plant G.,
RA Ghiso J.;
RT "A stop-codon mutation in the BRI gene associated with familial British
RT dementia.";
RL Nature 399:776-781(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN CAA-ITM2B2, AND VARIANT
RP CAA-ITM2B2 SER-266 DELINS PHE-ASN-LEU-PHE-LEU-ASN-SER-GLN-GLU-LYS-HIS-TYR.
RX PubMed=10781099; DOI=10.1073/pnas.080076097;
RA Vidal R., Revesz T., Rostagno A., Kim E., Holton J.L., Bek T.,
RA Bojsen-Moeller M., Braendgaard H., Plant G., Ghiso J., Frangione B.;
RT "A decamer duplication in the 3' region of the BRI gene originates an
RT amyloid peptide that is associated with dementia in a Danish kindred.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:4920-4925(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Adrenal gland;
RA Ren S., Shi J., Huang C., Jiang C., Li Y., Zhou J., Yu Y., Xu S., Wang Y.,
RA Fu G., Chen Z., Han Z.;
RT "A novel gene expressed in human adrenal gland.";
RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W.,
RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J.,
RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z.,
RA Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis
RT and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-15.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-15.
RC TISSUE=Brain, and Uterus;
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 INVOLVEMENT IN RDGCA, AND VARIANT RDGCA ALA-261.
RX PubMed=24026677; DOI=10.1093/hmg/ddt439;
RA Audo I., Bujakowska K., Orhan E., El Shamieh S., Sennlaub F.,
RA Guillonneau X., Antonio A., Michiels C., Lancelot M.E., Letexier M.,
RA Saraiva J.P., Nguyen H., Luu T.D., Leveillard T., Poch O., Dollfus H.,
RA Paques M., Goureau O., Mohand-Said S., Bhattacharya S.S., Sahel J.A.,
RA Zeitz C.;
RT "The familial dementia gene revisited: a missense mutation revealed by
RT whole-exome sequencing identifies ITM2B as a candidate gene underlying a
RT novel autosomal dominant retinal dystrophy in a large family.";
RL Hum. Mol. Genet. 23:491-501(2014).
RN [10]
RP CHARACTERIZATION OF VARIANT CAA-ITM2B1
RP ARG-THR-VAL-LYS-LYS-ASN-ILE-ILE-GLU-GLU-ASN-266 INS, TOPOLOGY, CLEAVAGE BY
RP FURIN, SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=10526337; DOI=10.1038/14783;
RA Kim S.H., Wang R., Gordon D.J., Bass J., Steiner D.F., Lynn D.G.,
RA Thinakaran G., Meredith S.C., Sisodia S.S.;
RT "Furin mediates enhanced production of fibrillogenic ABri peptides in
RT familial British dementia.";
RL Nat. Neurosci. 2:984-988(1999).
RN [11]
RP FUNCTION, TOPOLOGY, PROTEOLYTIC CLEAVAGE, CHARACTERIZATION OF VARIANT
RP CAA-ITM2B1 ARG-THR-VAL-LYS-LYS-ASN-ILE-ILE-GLU-GLU-ASN-266 INS,
RP CHARACTERIZATION OF VARIANT CAA-ITM2B2 SER-266 DELINS
RP PHE-ASN-LEU-PHE-LEU-ASN-SER-GLN-GLU-LYS-HIS-TYR, AND SUBCELLULAR LOCATION.
RX PubMed=14656991; DOI=10.1096/fj.03-0730fje;
RA Choi S.I., Vidal R., Frangione B., Levy E.;
RT "Axonal transport of British and Danish amyloid peptides via secretory
RT vesicles.";
RL FASEB J. 18:373-375(2004).
RN [12]
RP FUNCTION, AND INTERACTION WITH APP.
RX PubMed=15983050; DOI=10.1074/jbc.c500217200;
RA Matsuda S., Giliberto L., Matsuda Y., Davies P., McGowan E., Pickford F.,
RA Ghiso J., Frangione B., D'Adamio L.;
RT "The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta
RT precursor protein and inhibits amyloid-beta production.";
RL J. Biol. Chem. 280:28912-28916(2005).
RN [13]
RP FUNCTION, AND INTERACTION WITH APP.
RX PubMed=16027166; DOI=10.1074/jbc.c500231200;
RA Fotinopoulou A., Tsachaki M., Vlavaki M., Poulopoulos A., Rostagno A.,
RA Frangione B., Ghiso J., Efthimiopoulos S.;
RT "BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid
RT beta (Abeta) production.";
RL J. Biol. Chem. 280:30768-30772(2005).
RN [14]
RP CHARACTERIZATION OF VARIANT CAA-ITM2B2 SER-266 DELINS
RP PHE-ASN-LEU-PHE-LEU-ASN-SER-GLN-GLU-LYS-HIS-TYR.
RX PubMed=16091362; DOI=10.1074/jbc.m504038200;
RA Tomidokoro Y., Lashley T., Rostagno A., Neubert T.A., Bojsen-Moller M.,
RA Braendgaard H., Plant G., Holton J., Frangione B., Revesz T., Ghiso J.;
RT "Familial Danish dementia: co-existence of Danish and Alzheimer amyloid
RT subunits (ADan AND A{beta}) in the absence of compact plaques.";
RL J. Biol. Chem. 280:36883-36894(2005).
RN [15]
RP SUBCELLULAR LOCATION, TOPOLOGY, CLEAVAGE BY ADAM10; FURIN; SPPL2A AND
RP SPPL2B, INTERACTION WITH SPPL2A AND SPPL2B, AND MUTAGENESIS OF
RP 243-ARG-GLU-244.
RX PubMed=17965014; DOI=10.1074/jbc.m706661200;
RA Martin L., Fluhrer R., Reiss K., Kremmer E., Saftig P., Haass C.;
RT "Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and
RT SPPL2a/SPPL2b.";
RL J. Biol. Chem. 283:1644-1652(2008).
RN [16]
RP FUNCTION OF SECRETED BRI23 PEPTIDE, SUBCELLULAR LOCATION, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=18524908; DOI=10.1523/jneurosci.0891-08.2008;
RA Kim J., Miller V.M., Levites Y., West K.J., Zwizinski C.W., Moore B.D.,
RA Troendle F.J., Bann M., Verbeeck C., Price R.W., Smithson L., Sonoda L.,
RA Wagg K., Rangachari V., Zou F., Younkin S.G., Graff-Radford N., Dickson D.,
RA Rosenberry T., Golde T.E.;
RT "BRI2 (ITM2b) inhibits Abeta deposition in vivo.";
RL J. Neurosci. 28:6030-6036(2008).
RN [17]
RP FUNCTION.
RX PubMed=18753367; DOI=10.1523/jneurosci.2094-08.2008;
RA Matsuda S., Giliberto L., Matsuda Y., McGowan E.M., D'Adamio L.;
RT "BRI2 inhibits amyloid beta-peptide precursor protein processing by
RT interfering with the docking of secretases to the substrate.";
RL J. Neurosci. 28:8668-8676(2008).
RN [18]
RP CLEAVAGE BY ADAM10; FURIN AND SPPL2B, AND SUBCELLULAR LOCATION.
RX PubMed=19114711; DOI=10.1074/jbc.m807485200;
RA Martin L., Fluhrer R., Haass C.;
RT "Substrate requirements for SPPL2b-dependent regulated intramembrane
RT proteolysis.";
RL J. Biol. Chem. 284:5662-5670(2009).
RN [19]
RP FUNCTION OF SECRETED BRI23 PEPTIDE, SUBUNIT, INTERACTION WITH APP
RP AMYLOID-BETA PROTEIN 40, DISULFIDE BOND, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=20036644; DOI=10.1016/j.bbrc.2009.12.122;
RA Peng S., Fitzen M., Jornvall H., Johansson J.;
RT "The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1-23) and
RT amyloid beta-peptide (Abeta1-40): Implications for Bri2 effects on
RT processing of amyloid precursor protein and Abeta aggregation.";
RL Biochem. Biophys. Res. Commun. 393:356-361(2010).
RN [20]
RP SUBCELLULAR LOCATION, SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=18440095; DOI=10.1016/j.neurobiolaging.2008.03.004;
RA Tsachaki M., Ghiso J., Rostagno A., Efthimiopoulos S.;
RT "BRI2 homodimerizes with the involvement of intermolecular disulfide
RT bonds.";
RL Neurobiol. Aging 31:88-98(2010).
RN [21]
RP CLEAVAGE BY ADAM10; FURIN AND SPPL2B, GLYCOSYLATION AT ASN-170, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF ASN-170.
RX PubMed=21752865; DOI=10.1093/glycob/cwr097;
RA Tsachaki M., Serlidaki D., Fetani A., Zarkou V., Rozani I., Ghiso J.,
RA Efthimiopoulos S.;
RT "Glycosylation of BRI2 on asparagine 170 is involved in its trafficking to
RT the cell surface but not in its processing by furin or ADAM10.";
RL Glycobiology 21:1382-1388(2011).
RN [22]
RP FUNCTION OF MBRI2 IN APP PROCESSING INHIBITION, INTERACTION WITH APP
RP AMYLOID-BETA A4 AND APP C99, PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF 243-ARG-GLU-244.
RX PubMed=19748705; DOI=10.1016/j.neurobiolaging.2009.08.005;
RA Matsuda S., Matsuda Y., Snapp E.L., D'Adamio L.;
RT "Maturation of BRI2 generates a specific inhibitor that reduces APP
RT processing at the plasma membrane and in endocytic vesicles.";
RL Neurobiol. Aging 32:1400-1408(2011).
RN [23]
RP FUNCTION OF MBRI2 IN APP PROCESSING INHIBITION, AND INTERACTION WITH APP
RP AMYLOID-BETA A4 AND APP C99.
RX PubMed=22170863; DOI=10.1002/emmm.201100195;
RA Tamayev R., Matsuda S., Arancio O., D'Adamio L.;
RT "beta- but not gamma-secretase proteolysis of APP causes synaptic and
RT memory deficits in a mouse model of dementia.";
RL EMBO Mol. Med. 4:171-179(2012).
RN [24]
RP CLEAVAGE BY SPPL2A AND SPPL2B, AND MUTAGENESIS OF GLY-60.
RX PubMed=22194595; DOI=10.1074/jbc.m111.328104;
RA Fluhrer R., Martin L., Klier B., Haug-Kroper M., Grammer G., Nuscher B.,
RA Haass C.;
RT "The alpha-helical content of the transmembrane domain of the British
RT dementia protein-2 (Bri2) determines its processing by signal peptide
RT peptidase-like 2b (SPPL2b).";
RL J. Biol. Chem. 287:5156-5163(2012).
CC -!- FUNCTION: Plays a regulatory role in the processing of the amyloid-beta
CC A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta
CC peptide aggregation and fibrils deposition. Plays a role in the
CC induction of neurite outgrowth. Functions as a protease inhibitor by
CC blocking access of secretases to APP cleavage sites.
CC -!- FUNCTION: Mature BRI2 (mBRI2) functions as a modulator of the amyloid-
CC beta A4 precursor protein (APP) processing leading to a strong
CC reduction in the secretion of secretase-processed amyloid-beta protein
CC 40 and amyloid-beta protein 42.
CC -!- FUNCTION: Bri23 peptide prevents aggregation of APP amyloid-beta
CC protein 42 into toxic oligomers.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B.
CC Interacts with APP. Mature BRI2 (mBRI2) interacts with the APP amyloid-
CC beta A4 protein; the interaction occurs at the cell surface and in the
CC endocytic compartments and enable alpha- and beta-secretase-induced APP
CC cleavage inhibition. Mature BRI2 (mBRI2) interacts with the APP C99;
CC the interaction occurs in the endocytic compartments and enable gamma-
CC secretase-induced C99 cleavage inhibition. May form heterodimers with
CC Bri23 peptide and APP amyloid-beta protein 40.
CC {ECO:0000269|PubMed:15983050, ECO:0000269|PubMed:16027166,
CC ECO:0000269|PubMed:17965014, ECO:0000269|PubMed:18440095,
CC ECO:0000269|PubMed:19748705, ECO:0000269|PubMed:20036644,
CC ECO:0000269|PubMed:22170863}.
CC -!- INTERACTION:
CC Q9Y287; P05067: APP; NbExp=4; IntAct=EBI-2866431, EBI-77613;
CC Q9Y287; P05067-8: APP; NbExp=4; IntAct=EBI-2866431, EBI-302661;
CC Q9Y287; P56817: BACE1; NbExp=4; IntAct=EBI-2866431, EBI-2433139;
CC Q9Y287; Q8N6L0: KASH5; NbExp=3; IntAct=EBI-2866431, EBI-749265;
CC Q9Y287; P26715: KLRC1; NbExp=3; IntAct=EBI-2866431, EBI-9018187;
CC Q9Y287; Q58DX5: NAALADL2; NbExp=3; IntAct=EBI-2866431, EBI-10178964;
CC Q9Y287; Q96E17: RAB3C; NbExp=3; IntAct=EBI-2866431, EBI-4287022;
CC Q9Y287; Q9NRM0-1: SLC2A9; NbExp=4; IntAct=EBI-2866431, EBI-25396304;
CC Q9Y287; Q9NRM0-2: SLC2A9; NbExp=2; IntAct=EBI-2866431, EBI-25396386;
CC Q9Y287; Q8N205: SYNE4; NbExp=3; IntAct=EBI-2866431, EBI-7131783;
CC -!- SUBCELLULAR LOCATION: [Integral membrane protein 2B]: Golgi apparatus
CC membrane {ECO:0000269|PubMed:14656991, ECO:0000269|PubMed:19114711};
CC Single-pass type II membrane protein {ECO:0000269|PubMed:10526337}.
CC Note=Immature BRI2 (imBRI2) is cleaved by furin in the Golgi into mBRI2
CC and a Bri23 peptide. mBRI2 is transported to the plasma membrane and
CC Bri23 peptide is secreted.
CC -!- SUBCELLULAR LOCATION: [BRI2, membrane form]: Cell membrane
CC {ECO:0000269|PubMed:18440095, ECO:0000269|PubMed:19748705,
CC ECO:0000269|PubMed:21752865}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:10526337}. Endosome membrane
CC {ECO:0000269|PubMed:19748705}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:10526337}. Note=Mature BRI2 (mBRI2) needs to be
CC transported from the endoplasmic reticulum compartment to the cell
CC membrane in order to be able to inhibit APP processing.
CC {ECO:0000269|PubMed:19748705}.
CC -!- SUBCELLULAR LOCATION: [Bri23 peptide]: Secreted
CC {ECO:0000269|PubMed:10526337, ECO:0000269|PubMed:14656991,
CC ECO:0000269|PubMed:18524908}. Note=Detected in the cerebral spinal
CC fluid (CSF). {ECO:0000269|PubMed:18524908}.
CC -!- SUBCELLULAR LOCATION: [BRI2C, soluble form]: Secreted
CC {ECO:0000269|PubMed:17965014}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y287-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y287-2; Sequence=VSP_055326;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Expressed in brain.
CC -!- PTM: The ectodomain C-terminal part of the imBRI2 is processed by furin
CC producing a secreted Bri23 peptide and a mature BRI2, membrane form
CC (mBRI2). The remaining part of the ectodomain of mBRI2 containing the
CC BRICHOS domain is cleaved by ADAM10 and is secreted (BRI2C, soluble
CC form). The membrane-bound N-terminal fragment (BRI2C, membrane form) is
CC further proteolytically processed by SPPL2A and SPPL2B through
CC regulated intramembrane proteolysis producing a secreted C-peptide and
CC a BRI2 intracellular domain (BRI2 ICD) released in the cytosol.
CC Shedding by ADAM10 facilitates intramembrane cleavage but is not
CC absolutely required for BRI2 ICD generation.
CC -!- PTM: Glycosylation at Asn-170 is important for cell surface
CC localization, but doesn't affect furin- and ADAM10-induced proteolytic
CC processing. {ECO:0000269|PubMed:21752865}.
CC -!- DISEASE: Cerebral amyloid angiopathy, ITM2B-related 1 (CAA-ITM2B1)
CC [MIM:176500]: A disorder characterized by amyloid deposition in the
CC walls of cerebral blood vessels and neurodegeneration in the central
CC nervous system. Cerebral amyloid angiopathy, non-neuritic and
CC perivascular plaques and neurofibrillary tangles are the predominant
CC pathological lesions. Clinical features include progressive mental
CC deterioration, spasticity and muscular rigidity.
CC {ECO:0000269|PubMed:10391242, ECO:0000269|PubMed:10526337,
CC ECO:0000269|PubMed:14656991}. Note=The disease is caused by variants
CC affecting the gene represented in this entry. A single base
CC substitution at the stop codon of ITM2B generates a 277-residue
CC precursor that is cleaved at the normal furin processing site to
CC generate the ABri amyloidogenic peptide (PubMed:10391242). ABri
CC accumulates in the brain and produces amyloid fibrils responsible for
CC neuronal dysfunction and dementia. ABri peptide variant forms fibrils
CC in vitro (PubMed:10526337). {ECO:0000269|PubMed:10391242,
CC ECO:0000269|PubMed:10526337}.
CC -!- DISEASE: Cerebral amyloid angiopathy, ITM2B-related 2 (CAA-ITM2B2)
CC [MIM:117300]: A disorder characterized by amyloid deposition in the
CC walls of the blood vessels of the cerebrum, choroid plexus, cerebellum,
CC spinal cord and retina. Plaques and neurofibrillary tangles are
CC observed in the hippocampus. Clinical features include progressive
CC ataxia, dementia, cataracts and deafness. {ECO:0000269|PubMed:10781099,
CC ECO:0000269|PubMed:14656991, ECO:0000269|PubMed:16091362}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. A decamer duplication in the 3' region of ITM2B results in the
CC production of the ADan amyloidogenic peptide (PubMed:10781099). ADan is
CC generated by cleavage of the mutated precursor at the normal furin
CC processing site. ADan accumulates in the brain and produces amyloid
CC fibrils responsible for neuronal dysfunction and dementia.
CC {ECO:0000269|PubMed:10781099}.
CC -!- DISEASE: Retinal dystrophy with inner retinal dysfunction and ganglion
CC cell abnormalities (RDGCA) [MIM:616079]: An autosomal dominant retinal
CC dystrophy characterized by inner retinal dysfunction in association
CC with ganglion cell abnormalities. Clinical features include mild
CC photophobia, progressive loss of central vision, night blindness, and
CC hyperreflectivity of nerve and ganglion cell layers.
CC {ECO:0000269|PubMed:24026677}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ITM2 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/itm2b/";
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DR EMBL; AF152462; AAD45280.1; -; mRNA.
DR EMBL; AF246221; AAF66130.1; -; mRNA.
DR EMBL; AF136973; AAG49434.1; -; mRNA.
DR EMBL; AF092128; AAD40370.1; -; mRNA.
DR EMBL; BT006863; AAP35509.1; -; mRNA.
DR EMBL; AY341247; AAP88930.1; -; Genomic_DNA.
DR EMBL; CH471075; EAX08789.1; -; Genomic_DNA.
DR EMBL; CH471075; EAX08790.1; -; Genomic_DNA.
DR EMBL; BC000554; AAH00554.1; -; mRNA.
DR EMBL; BC016148; AAH16148.1; -; mRNA.
DR CCDS; CCDS9409.1; -. [Q9Y287-1]
DR RefSeq; NP_068839.1; NM_021999.4. [Q9Y287-1]
DR AlphaFoldDB; Q9Y287; -.
DR BioGRID; 114835; 130.
DR IntAct; Q9Y287; 47.
DR MINT; Q9Y287; -.
DR STRING; 9606.ENSP00000367828; -.
DR TCDB; 1.C.81.2.1; the arenicin (arenicin) family.
DR GlyConnect; 1403; 2 N-Linked glycans (1 site).
DR GlyGen; Q9Y287; 1 site, 2 N-linked glycans (1 site).
DR iPTMnet; Q9Y287; -.
DR PhosphoSitePlus; Q9Y287; -.
DR SwissPalm; Q9Y287; -.
DR BioMuta; ITM2B; -.
DR DMDM; 12643343; -.
DR EPD; Q9Y287; -.
DR jPOST; Q9Y287; -.
DR MassIVE; Q9Y287; -.
DR MaxQB; Q9Y287; -.
DR PaxDb; Q9Y287; -.
DR PeptideAtlas; Q9Y287; -.
DR PRIDE; Q9Y287; -.
DR ProteomicsDB; 85699; -. [Q9Y287-1]
DR TopDownProteomics; Q9Y287-1; -. [Q9Y287-1]
DR Antibodypedia; 23811; 262 antibodies from 31 providers.
DR DNASU; 9445; -.
DR Ensembl; ENST00000378549.5; ENSP00000367811.5; ENSG00000136156.15. [Q9Y287-2]
DR Ensembl; ENST00000647800.2; ENSP00000497221.1; ENSG00000136156.15. [Q9Y287-1]
DR GeneID; 9445; -.
DR KEGG; hsa:9445; -.
DR MANE-Select; ENST00000647800.2; ENSP00000497221.1; NM_021999.5; NP_068839.1.
DR UCSC; uc001vbz.4; human. [Q9Y287-1]
DR CTD; 9445; -.
DR DisGeNET; 9445; -.
DR GeneCards; ITM2B; -.
DR HGNC; HGNC:6174; ITM2B.
DR HPA; ENSG00000136156; Low tissue specificity.
DR MalaCards; ITM2B; -.
DR MIM; 117300; phenotype.
DR MIM; 176500; phenotype.
DR MIM; 603904; gene.
DR MIM; 616079; phenotype.
DR neXtProt; NX_Q9Y287; -.
DR OpenTargets; ENSG00000136156; -.
DR Orphanet; 97345; ABri amyloidosis.
DR Orphanet; 97346; ADan amyloidosis.
DR Orphanet; 397758; Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies.
DR PharmGKB; PA29971; -.
DR VEuPathDB; HostDB:ENSG00000136156; -.
DR eggNOG; KOG4681; Eukaryota.
DR GeneTree; ENSGT00950000183115; -.
DR HOGENOM; CLU_074596_0_0_1; -.
DR InParanoid; Q9Y287; -.
DR OMA; YFAFQQD; -.
DR OrthoDB; 1322680at2759; -.
DR PhylomeDB; Q9Y287; -.
DR TreeFam; TF317770; -.
DR PathwayCommons; Q9Y287; -.
DR Reactome; R-HSA-977225; Amyloid fiber formation.
DR SignaLink; Q9Y287; -.
DR BioGRID-ORCS; 9445; 44 hits in 1082 CRISPR screens.
DR ChiTaRS; ITM2B; human.
DR GeneWiki; ITM2B; -.
DR GenomeRNAi; 9445; -.
DR Pharos; Q9Y287; Tbio.
DR PRO; PR:Q9Y287; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; Q9Y287; protein.
DR Bgee; ENSG00000136156; Expressed in renal glomerulus and 204 other tissues.
DR ExpressionAtlas; Q9Y287; baseline and differential.
DR Genevisible; Q9Y287; HS.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030660; C:Golgi-associated vesicle membrane; IDA:UniProtKB.
DR GO; GO:0031301; C:integral component of organelle membrane; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0001540; F:amyloid-beta binding; IPI:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:Ensembl.
DR GO; GO:0042985; P:negative regulation of amyloid precursor protein biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR InterPro; IPR007084; BRICHOS_dom.
DR InterPro; IPR040145; ITM2.
DR PANTHER; PTHR10962; PTHR10962; 1.
DR Pfam; PF04089; BRICHOS; 1.
DR SMART; SM01039; BRICHOS; 1.
DR PROSITE; PS50869; BRICHOS; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Amyloid; Amyloidosis; Cell membrane;
KW Cleavage on pair of basic residues; Deafness; Disease variant;
KW Disulfide bond; Endosome; Glycoprotein; Golgi apparatus; Membrane;
KW Neurodegeneration; Reference proteome; Secreted; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..266
FT /note="Integral membrane protein 2B"
FT /id="PRO_0000045840"
FT CHAIN 1..243
FT /note="BRI2, membrane form"
FT /id="PRO_0000417464"
FT CHAIN 1..?
FT /note="BRI2 intracellular domain"
FT /id="PRO_0000417465"
FT CHAIN ?..243
FT /note="BRI2C, soluble form"
FT /id="PRO_0000417466"
FT PEPTIDE 244..266
FT /note="Bri23 peptide"
FT /id="PRO_0000016545"
FT TOPO_DOM 1..54
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 55..75
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 76..266
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 137..231
FT /note="BRICHOS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00255"
FT REGION 102..134
FT /note="Necessary for interaction with APP and inhibitor
FT effects on APP processing"
FT SITE 243..244
FT /note="Cleavage; by furin"
FT CARBOHYD 170
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21752865"
FT DISULFID 89
FT /note="Interchain"
FT DISULFID 164..223
FT /evidence="ECO:0000250"
FT DISULFID 248..265
FT /note="Interchain (between ADan peptide variants)"
FT VAR_SEQ 83..188
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_055326"
FT VARIANT 15
FT /note="A -> T (in dbSNP:rs11556905)"
FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.5"
FT /id="VAR_071047"
FT VARIANT 261
FT /note="E -> A (in RDGCA; dbSNP:rs606231283)"
FT /evidence="ECO:0000269|PubMed:24026677"
FT /id="VAR_072434"
FT VARIANT 266
FT /note="S -> FNLFLNSQEKHY (in CAA-ITM2B2; amyloid ADan;
FT colocalizes with APP amyloid-beta protein 42 in parenchymal
FT and vascular lesions; interacts with APP amyloid-beta
FT protein 42; oligomerizes and is subjected to disulfide bond
FT formation; undergoes cyclic pyroglutamate formation on the
FT N-terminus Gln residues and is further proteolytically
FT cleaved in the cerebral cortex)"
FT /evidence="ECO:0000269|PubMed:10781099,
FT ECO:0000269|PubMed:14656991, ECO:0000269|PubMed:16091362"
FT /id="VAR_010240"
FT VARIANT 266
FT /note="S -> SRTVKKNIIEEN (in CAA-ITM2B1; amyloid ABri)"
FT /evidence="ECO:0000269|PubMed:10391242,
FT ECO:0000269|PubMed:10526337, ECO:0000269|PubMed:14656991"
FT /id="VAR_010239"
FT MUTAGEN 60
FT /note="G->V: Reduces strongly intramembrane cleavage by
FT SPPL2B."
FT /evidence="ECO:0000269|PubMed:22194595"
FT MUTAGEN 170
FT /note="N->A: Accumulates in intracellular compartments.
FT Does not inhibit furin, ADAM10 and SPPL2A extracellular
FT proteolytic processing activity."
FT /evidence="ECO:0000269|PubMed:21752865"
FT MUTAGEN 243..244
FT /note="RE->AA: Inhibits cleavage by furin. Does not prevent
FT ADAM10 shedding."
FT /evidence="ECO:0000269|PubMed:17965014,
FT ECO:0000269|PubMed:19748705"
SQ SEQUENCE 266 AA; 30338 MW; 3A7D8CA259F1F627 CRC64;
MVKVTFNSAL AQKEAKKDEP KSGEEALIIP PDAVAVDCKD PDDVVPVGQR RAWCWCMCFG
LAFMLAGVIL GGAYLYKYFA LQPDDVYYCG IKYIKDDVIL NEPSADAPAA LYQTIEENIK
IFEEEEVEFI SVPVPEFADS DPANIVHDFN KKLTAYLDLN LDKCYVIPLN TSIVMPPRNL
LELLINIKAG TYLPQSYLIH EHMVITDRIE NIDHLGFFIY RLCHDKETYK LQRRETIKGI
QKREASNCFA IRHFENKFAV ETLICS
