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Database: UniProt
Entry: Q9UM47
LinkDB: Q9UM47
Original site: Q9UM47 
ID   NOTC3_HUMAN             Reviewed;        2321 AA.
AC   Q9UM47; Q9UEB3; Q9UPL3; Q9Y6L8;
DT   27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT   08-FEB-2011, sequence version 2.
DT   13-FEB-2019, entry version 198.
DE   RecName: Full=Neurogenic locus notch homolog protein 3;
DE            Short=Notch 3;
DE   Contains:
DE     RecName: Full=Notch 3 extracellular truncation;
DE   Contains:
DE     RecName: Full=Notch 3 intracellular domain;
DE   Flags: Precursor;
GN   Name=NOTCH3;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-2223.
RX   PubMed=8878478; DOI=10.1038/383707a0;
RA   Joutel A., Corpechot C., Ducros A., Vahedi K., Chabriat H., Mouton P.,
RA   Alamowitch S., Domenga V., Cecillion M., Marechal E., Maciazek J.,
RA   Vayssiere C., Cruaud C., Cabanis E.-A., Ruchoux M.M., Weissenbach J.,
RA   Bach J.-F., Bousser M.-G., Tournier-Lasserve E.;
RT   "Notch3 mutations in CADASIL, a hereditary adult-onset condition
RT   causing stroke and dementia.";
RL   Nature 383:707-710(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Gunel M., Artavanis-Tsakonas S.;
RL   Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA   Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA   Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA   Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA   Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA   Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA   Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA   Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA   Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA   Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA   Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA   Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA   Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA   Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA   Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA   Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [4]
RP   IDENTIFICATION OF LIGANDS.
RX   PubMed=10079256; DOI=10.1016/S0002-9440(10)65325-4;
RA   Gray G.E., Mann R.S., Mitsiadis E., Henrique D., Carcangiu M.-L.,
RA   Banks A., Leiman J., Ward D., Ish-Horowitz D., Artavanis-Tsakonas S.;
RT   "Human ligands of the Notch receptor.";
RL   Am. J. Pathol. 154:785-794(1999).
RN   [5]
RP   INTERACTION WITH MAML1.
RX   PubMed=11101851; DOI=10.1038/82644;
RA   Wu L., Aster J.C., Blacklow S.C., Lake R., Artavanis-Tsakonas S.,
RA   Griffin J.D.;
RT   "MAML1, a human homologue of Drosophila mastermind, is a
RT   transcriptional co-activator for NOTCH receptors.";
RL   Nat. Genet. 26:484-489(2000).
RN   [6]
RP   INTERACTION WITH MAML2 AND MAML3.
RX   PubMed=12370315; DOI=10.1128/MCB.22.21.7688-7700.2002;
RA   Wu L., Sun T., Kobayashi K., Gao P., Griffin J.D.;
RT   "Identification of a family of mastermind-like transcriptional
RT   coactivators for mammalian notch receptors.";
RL   Mol. Cell. Biol. 22:7688-7700(2002).
RN   [7]
RP   INTERACTION WITH PSMA1.
RX   PubMed=17292860; DOI=10.1016/j.bbrc.2007.01.151;
RA   Zhang Y., Jia L., Lee S.J., Wang M.M.;
RT   "Conserved signal peptide of Notch3 inhibits interaction with
RT   proteasome.";
RL   Biochem. Biophys. Res. Commun. 355:245-251(2007).
RN   [8]
RP   INTERACTION WITH HIF1AN.
RX   PubMed=17573339; DOI=10.1074/jbc.M704102200;
RA   Coleman M.L., McDonough M.A., Hewitson K.S., Coles C., Mecinovic J.,
RA   Edelmann M., Cook K.M., Cockman M.E., Lancaster D.E., Kessler B.M.,
RA   Oldham N.J., Ratcliffe P.J., Schofield C.J.;
RT   "Asparaginyl hydroxylation of the Notch ankyrin repeat domain by
RT   factor inhibiting hypoxia-inducible factor.";
RL   J. Biol. Chem. 282:24027-24038(2007).
RN   [9]
RP   HYDROXYLATION BY HIF1AN.
RX   PubMed=18299578; DOI=10.1073/pnas.0711591105;
RA   Zheng X., Linke S., Dias J.M., Zheng X., Gradin K., Wallis T.P.,
RA   Hamilton B.R., Gustafsson M., Ruas J.L., Wilkins S., Bilton R.L.,
RA   Brismar K., Whitelaw M.L., Pereira T., Gorman J.J., Ericson J.,
RA   Peet D.J., Lendahl U., Poellinger L.;
RT   "Interaction with factor inhibiting HIF-1 defines an additional mode
RT   of cross-coupling between the Notch and hypoxia signaling pathways.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:3368-3373(2008).
RN   [10]
RP   METHYLATION [LARGE SCALE ANALYSIS] AT ARG-2174, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Colon carcinoma;
RX   PubMed=24129315; DOI=10.1074/mcp.O113.027870;
RA   Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V.,
RA   Aguiar M., Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C.,
RA   Vemulapalli V., Bedford M.T., Comb M.J.;
RT   "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT   methylation.";
RL   Mol. Cell. Proteomics 13:372-387(2014).
RN   [11]
RP   INVOLVEMENT IN LMNS.
RX   PubMed=25394726; DOI=10.1002/ajmg.a.36863;
RA   Gripp K.W., Robbins K.M., Sobreira N.L., Witmer P.D., Bird L.M.,
RA   Avela K., Makitie O., Alves D., Hogue J.S., Zackai E.H., Doheny K.F.,
RA   Stabley D.L., Sol-Church K.;
RT   "Truncating mutations in the last exon of NOTCH3 cause lateral
RT   meningocele syndrome.";
RL   Am. J. Med. Genet. A 167A:271-281(2015).
RN   [12]
RP   VARIANTS CADASIL1 TYR-49; CYS-71; CYS-90; CYS-110; CYS-133; CYS-141;
RP   ARG-146; CYS-153; CYS-169; CYS-171; CYS-182; ARG-185; SER-212;
RP   GLY-222; TYR-224; CYS-258; TYR-542; CYS-558; CYS-578; CYS-728;
RP   CYS-985; CYS-1006; CYS-1031; CYS-1231 AND ARG-1261, AND VARIANTS
RP   ARG-170; LEU-496; GLN-1133; MET-1183 AND VAL-2223.
RX   PubMed=9388399; DOI=10.1016/S0140-6736(97)08083-5;
RA   Joutel A., Vahedi K., Corpechot C., Troesch A., Chabriat H.,
RA   Vayssiere C., Cruaud C., Maciazek J., Weissenbach J., Bousser M.-G.,
RA   Bach J.-F., Tournier-Lasserve E.;
RT   "Strong clustering and stereotyped nature of Notch3 mutations in
RT   CADASIL patients.";
RL   Lancet 350:1511-1515(1997).
RN   [13]
RP   VARIANTS CADASIL1 CYS-90; PHE-117; CYS-133; CYS-141; CYS-169; TYR-174;
RP   CYS-182 AND ARG-183.
RX   PubMed=10227618; DOI=10.1212/WNL.52.7.1361;
RA   Dichgans M., Filippi M., Bruening R., Iannucci G., Berchtenbreiter C.,
RA   Minicucci L., Uttner I., Crispin A., Ludwig H., Gasser T.,
RA   Yousry T.A.;
RT   "Quantitative MRI in CADASIL: correlation with disability and
RT   cognitive performance.";
RL   Neurology 52:1361-1367(1999).
RN   [14]
RP   VARIANTS CADASIL1 CYS-133; CYS-141; CYS-153; CYS-182; CYS-207; CYS-544
RP   AND ARG-1015.
RX   PubMed=10371548; DOI=10.1212/WNL.52.9.1913;
RG   Dutch CADASIL research group;
RA   Lesnik Oberstein S.A.J., Ferrari M.D., Bakker E., van Gestel J.,
RA   Kneppers A.L.J., Frants R.R., Breuning M.H., Haan J.;
RT   "Diagnostic Notch3 sequence analysis in CADASIL: three new mutations
RT   in Dutch patients. Dutch CADASIL Research Group.";
RL   Neurology 52:1913-1915(1999).
RN   [15]
RP   VARIANTS CADASIL1 80-ASP--SER-84 DEL; CYS-90; PHE-93; CYS-110;
RP   PHE-117; PHE-123; CYS-133; CYS-141; SER-144; TYR-144; CYS-150;
RP   153-ARG--CYS-155 DEL; CYS-153; CYS-169; TYR-174; CYS-182; ARG-183;
RP   SER-183; ARG-185 AND PHE-194.
RX   PubMed=10854111; DOI=10.1038/sj.ejhg.5200460;
RA   Dichgans M., Ludwig H., Mueller-Hoecker J., Messerschmidt A.,
RA   Gasser T.;
RT   "Small in-frame deletions and missense mutations in CADASIL: 3D models
RT   predict misfolding of Notch3 EGF-like repeat domains.";
RL   Eur. J. Hum. Genet. 8:280-285(2000).
RN   [16]
RP   VARIANT CADASIL1 PHE-144.
RX   PubMed=11058919;
RX   DOI=10.1002/1098-1004(200011)16:5<449::AID-HUMU26>3.3.CO;2-9;
RA   Grigg R., Lea R., Sullivan A.A., Curtain R., MacMillian J.,
RA   Griffiths L.;
RT   "Identification of a novel mutation C144F in the Notch3 gene in an
RT   Australian CADASIL pedigree.";
RL   Hum. Mutat. 16:449-450(2000).
RN   [17]
RP   VARIANTS CADASIL1 TYR-49; CYS-54; CYS-90; CYS-110; 114-GLY--PRO-120
RP   DEL; TYR-123; CYS-133; CYS-141; ARG-146; CYS-153; SER-162; CYS-169;
RP   TYR-174; CYS-180; CYS-182; ARG-185; TYR-194; TYR-206; CYS-207;
RP   SER-212; GLY-222; TYR-224; CYS-258; TYR-542; CYS-558; CYS-578;
RP   CYS-607; CYS-728; CYS-984; CYS-985; CYS-1006; CYS-1031; CYS-1231 AND
RP   ARG-1261.
RX   PubMed=11102981;
RX   DOI=10.1002/1098-1004(200012)16:6<518::AID-HUMU9>3.3.CO;2-H;
RA   Escary J.-L., Cecillon M., Maciazek J., Lathrop M.,
RA   Tournier-Lasserve E., Joutel A.;
RT   "Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene
RT   with a high G-C content.";
RL   Hum. Mutat. 16:518-526(2000).
RN   [18]
RP   VARIANT CADASIL1 114-GLY--PRO-120 DEL.
RX   PubMed=10802807; DOI=10.1212/WNL.54.9.1874;
RA   Joutel A., Chabriat H., Vahedi K., Domenga V., Vayssiere C.,
RA   Ruchoux M.M., Lucas C., Leys D., Bousser M.-G., Tournier-Lasserve E.;
RT   "Splice site mutation causing a seven amino acid Notch3 in-frame
RT   deletion in CADASIL.";
RL   Neurology 54:1874-1875(2000).
RN   [19]
RP   VARIANT CADASIL1 CYS-332.
RX   PubMed=11559313; DOI=10.1001/archneur.58.9.1418;
RA   Oliveri R.L., Muglia M., De Stefano N., Mazzei R., Labate A.,
RA   Conforti F.L., Patitucci A., Gabriele A.L., Tagarelli G.,
RA   Magariello A., Zappia M., Gambardella A., Federico A., Quattrone A.;
RT   "A novel mutation in the Notch3 gene in an Italian family with
RT   cerebral autosomal dominant arteriopathy with subcortical infarcts and
RT   leukoencephalopathy: genetic and magnetic resonance spectroscopic
RT   findings.";
RL   Arch. Neurol. 58:1418-1422(2001).
RN   [20]
RP   VARIANTS CADASIL1 CYS-110; CYS-133; TRP-134; CYS-141; CYS-153;
RP   CYS-182; GLY-185; CYS-207; SER-212; GLY-222; SER-428; CYS-558; CYS-985
RP   AND CYS-1063.
RX   PubMed=11755616; DOI=10.1016/S0140-6736(01)07142-2;
RA   Joutel A., Favrole P., Labauge P., Chabriat H., Lescoat C.,
RA   Andreux F., Domenga V., Cecillon M., Vahedi K., Ducros A.,
RA   Cave-Riant F., Bousser M.G., Tournier-Lasserve E.;
RT   "Skin biopsy immunostaining with a Notch3 monoclonal antibody for
RT   CADASIL diagnosis.";
RL   Lancet 358:2049-2051(2001).
RN   [21]
RP   VARIANT CADASIL1 TRP-134.
RX   PubMed=11810186; DOI=10.1007/s004010100439;
RA   Feuerhake F., Volk B., Ostertag C.B., Jungling F.D., Kassubek J.,
RA   Orszagh M., Dichgans M.;
RT   "Reversible coma with raised intracranial pressure: an unusual
RT   clinical manifestation of CADASIL.";
RL   Acta Neuropathol. 103:188-192(2002).
RN   [22]
RP   VARIANTS CADASIL1 ARG-76; TYR-93; TYR-128; CYS-142; ARG-194; TYR-222;
RP   SER-233; ARG-251; CYS-420; GLY-440; CYS-449; CYS-953 AND CYS-1021.
RX   PubMed=12146805;
RA   Kalimo H., Ruchoux M.-M., Viitanen M., Kalaria R.N.;
RT   "CADASIL: a common form of hereditary arteriopathy causing brain
RT   infarcts and dementia.";
RL   Brain Pathol. 12:371-384(2002).
RN   [23]
RP   VARIANT CADASIL1 ARG-455.
RX   PubMed=12136071; DOI=10.1212/WNL.59.2.277;
RA   Arboleda-Velasquez J.F., Lopera F., Lopez E., Frosch M.P.,
RA   Sepulveda-Falla D., Gutierrez J.E., Vargas S., Medina M.,
RA   Martinez De Arrieta C., Lebo R.V., Slaugenhaupt S.A., Betensky R.A.,
RA   Villegas A., Arcos-Burgos M., Rivera D., Restrepo J.C., Kosik K.S.;
RT   "C455R notch3 mutation in a Colombian CADASIL kindred with early onset
RT   of stroke.";
RL   Neurology 59:277-279(2002).
RN   [24]
RP   VARIANT CADASIL1 TYR-67.
RX   PubMed=12589106;
RA   Moon S.-Y., Kim H.-Y., Seok J.-I., Kwon J.-C., Ki C.-S., Kim J.-W.,
RA   Suh Y.-L., Na D.L.;
RT   "A novel mutation (C67Y)in the NOTCH3 gene in a Korean CADASIL
RT   patient.";
RL   J. Korean Med. Sci. 18:141-144(2003).
RN   [25]
RP   VARIANTS CADASIL1 CYS-90; CYS-133; CYS-169; ARG-174; PHE-174 AND
RP   LYS-213.
RX   PubMed=12810003; DOI=10.1016/S0022-510X(03)00109-6;
RA   Santa Y., Uyama E., Chui D.H., Arima M., Kotorii S., Takahashi K.,
RA   Tabira T.;
RT   "Genetic, clinical and pathological studies of CADASIL in Japan: a
RT   partial contribution of Notch3 mutations and implications of smooth
RT   muscle cell degeneration for the pathogenesis.";
RL   J. Neurol. Sci. 212:79-84(2003).
RN   [26]
RP   VARIANTS CADASIL1 ARG-76; CYS-90; CYS-110; CYS-141; CYS-153; CYS-169;
RP   CYS-182; ARG-183; CYS-189; SER-194; CYS-207; ARG-251; CYS-332;
RP   GLY-440; CYS-607; CYS-953 AND CYS-1231.
RX   PubMed=15229130; DOI=10.1093/brain/awh223;
RA   Singhal S., Bevan S., Barrick T., Rich P., Markus H.S.;
RT   "The influence of genetic and cardiovascular risk factors on the
RT   CADASIL phenotype.";
RL   Brain 127:2031-2038(2004).
RN   [27]
RP   VARIANTS CADASIL1 GLY-43; PHE-49; CYS-60; SER-65; TRP-76;
RP   77-GLN--CYS-82 DEL; 80-ASP--SER-84 DEL; ARG-87; TYR-87; CYS-90;
RP   PHE-93; TRP-106; TYR-108; CYS-110; PHE-117; PHE-123; CYS-133; TRP-134;
RP   CYS-141; SER-144; TYR-144; CYS-145; CYS-149; CYS-150; 153-ARG--155-CYS
RP   DEL; CYS-153; SER-155; CYS-169; ARG-174; TYR-174; CYS-182; ARG-183;
RP   SER-183; PHE-183; ARG-185; PHE-194; TYR-201; CYS-207; TYR-233;
RP   239-ASP--ASP-253 DEL; SER-240; ARG-245; TYR-260; CYS-332; CYS-335;
RP   CYS-337; SER-379; ARG-395; CYS-421; TYR-428; ARG-440; SER-446;
RP   TYR-484; TYR-495; ARG-511; TYR-549; CYS-558; CYS-985 AND TYR-1261.
RX   PubMed=15364702; DOI=10.1093/brain/awh282;
RA   Opherk C., Peters N., Herzog J., Luedtke R., Dichgans M.;
RT   "Long-term prognosis and causes of death in CADASIL: a retrospective
RT   study in 411 patients.";
RL   Brain 127:2533-2539(2004).
RN   [28]
RP   VARIANT CADASIL1 CYS-133.
RX   PubMed=15378071; DOI=10.1038/sj.ejhg.5201221;
RA   Mykkaenen K., Savontaus M.L., Juvonen V., Sistonen P., Tuisku S.,
RA   Tuominen S., Penttinen M., Lundkvist J., Viitanen M., Kalimo H.,
RA   Peoyhoenen M.;
RT   "Detection of the founder effect in Finnish CADASIL families.";
RL   Eur. J. Hum. Genet. 12:813-819(2004).
RN   [29]
RP   CHARACTERIZATION OF VARIANTS CADASIL1 CYS-133; SER-183 AND ARG-455,
RP   FUNCTION, SUBCELLULAR LOCATION, LIGAND-BINDING DOMAIN, AND PROTEOLYTIC
RP   PROCESSING.
RX   PubMed=15350543; DOI=10.1016/j.yexcr.2004.06.004;
RA   Peters N., Opherk C., Zacherle S., Capell A., Gempel P., Dichgans M.;
RT   "CADASIL-associated Notch3 mutations have differential effects both on
RT   ligand binding and ligand-induced Notch3 receptor signaling through
RT   RBP-Jk.";
RL   Exp. Cell Res. 299:454-464(2004).
RN   [30]
RP   VARIANT CADASIL1 TRP-108.
RX   PubMed=15300988;
RA   Rojas-Marcos I., Encarnacion M., Martinez-Yelamos S., Ferrer I.,
RA   Arbizu T., Gil-Peralta A., Garcia-Lozano J.R.;
RT   "Gene symbol: NOTCH3. Disease: CADASIL.";
RL   Hum. Genet. 115:175-175(2004).
RN   [31]
RP   VARIANTS CADASIL1 GLY-43; PHE-49; CYS-60; SER-65; TRP-76;
RP   80-ASP--SER-84 DEL; ARG-87; CYS-90; PHE-93; TYR-108; CYS-110; PHE-117;
RP   PHE-123; CYS-133; TRP-134; CYS-141; SER-144; TYR-144; CYS-149;
RP   CYS-150; CYS-153; 153-ARG--CYS-155 DEL; CYS-169; ARG-174; TYR-174;
RP   CYS-182; SER-183; PHE-183; ARG-185; PHE-194; CYS-207; TYR-233;
RP   SER-240; ARG-245; TYR-260; 239-ASP--ASP-253 DEL; CYS-319; CYS-332;
RP   CYS-335; CYS-337; SER-379; ARG-395; CYS-421; TYR-428; ARG-440;
RP   PHE-484; TYR-495; ARG-511; TYR-549; CYS-558; CYS-728; SER-775; CYS-985
RP   AND TYR-1261.
RX   PubMed=16009764; DOI=10.1001/archneur.62.7.1091;
RA   Peters N., Opherk C., Bergmann T., Castro M., Herzog J., Dichgans M.;
RT   "Spectrum of mutations in biopsy-proven CADASIL: implications for
RT   diagnostic strategies.";
RL   Arch. Neurol. 62:1091-1094(2005).
RN   [32]
RP   VARIANT CADASIL1 CYS-118.
RX   PubMed=15818833;
RA   Soong B.W., Lee Y.-C., Lu Y.-C.;
RT   "Gene symbol: NOTCH3. Disease: cerebral autosomal dominant
RT   arteriopathy with subcortical infarcts and leukoencephalopathy.";
RL   Hum. Genet. 116:242-242(2005).
RN   [33]
RP   VARIANT BRAIN SMALL-VESSEL-DISEASE PRO-1515.
RX   PubMed=18273901; DOI=10.1002/humu.9527;
RA   Fouillade C., Chabriat H., Riant F., Mine M., Arnoud M., Magy L.,
RA   Bousser M.G., Tournier-Lasserve E., Joutel A.;
RT   "Activating NOTCH3 mutation in a patient with small-vessel-disease of
RT   the brain.";
RL   Hum. Mutat. 29:452-452(2008).
RN   [34]
RP   VARIANT IMF2 PRO-1519.
RX   PubMed=23731542; DOI=10.1016/j.ajhg.2013.04.024;
RA   Martignetti J.A., Tian L., Li D., Ramirez M.C., Camacho-Vanegas O.,
RA   Camacho S.C., Guo Y., Zand D.J., Bernstein A.M., Masur S.K., Kim C.E.,
RA   Otieno F.G., Hou C., Abdel-Magid N., Tweddale B., Metry D.,
RA   Fournet J.C., Papp E., McPherson E.W., Zabel C., Vaksmann G.,
RA   Morisot C., Keating B., Sleiman P.M., Cleveland J.A., Everman D.B.,
RA   Zackai E., Hakonarson H.;
RT   "Mutations in PDGFRB cause autosomal-dominant infantile
RT   myofibromatosis.";
RL   Am. J. Hum. Genet. 92:1001-1007(2013).
RN   [35]
RP   VARIANT CADASIL1 CYS-710.
RX   PubMed=24000151; DOI=10.1002/humu.22432;
RA   Rutten J.W., Boon E.M., Liem M.K., Dauwerse J.G., Pont M.J.,
RA   Vollebregt E., Maat-Kievit A.J., Ginjaar H.B., Lakeman P.,
RA   van Duinen S.G., Terwindt G.M., Lesnik Oberstein S.A.;
RT   "Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.";
RL   Hum. Mutat. 34:1486-1489(2013).
CC   -!- FUNCTION: Functions as a receptor for membrane-bound ligands
CC       Jagged1, Jagged2 and Delta1 to regulate cell-fate determination
CC       (PubMed:15350543). Upon ligand activation through the released
CC       notch intracellular domain (NICD) it forms a transcriptional
CC       activator complex with RBPJ/RBPSUH and activates genes of the
CC       enhancer of split locus. Affects the implementation of
CC       differentiation, proliferation and apoptotic programs (By
CC       similarity). {ECO:0000250|UniProtKB:Q9R172,
CC       ECO:0000269|PubMed:15350543}.
CC   -!- SUBUNIT: Heterodimer of a C-terminal fragment N(TM) and a N-
CC       terminal fragment N(EC) which are probably linked by disulfide
CC       bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which
CC       act as transcriptional coactivators for NOTCH3. Interacts with
CC       PSMA1. Interacts with HIF1AN. {ECO:0000250,
CC       ECO:0000269|PubMed:11101851, ECO:0000269|PubMed:12370315,
CC       ECO:0000269|PubMed:17292860, ECO:0000269|PubMed:17573339}.
CC   -!- INTERACTION:
CC       Self; NbExp=2; IntAct=EBI-1236377, EBI-1236377;
CC       Q9R1P4:Psma1 (xeno); NbExp=2; IntAct=EBI-1236377, EBI-991653;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15350543};
CC       Single-pass type I membrane protein.
CC   -!- SUBCELLULAR LOCATION: Notch 3 intracellular domain: Nucleus.
CC       Note=Following proteolytical processing NICD is translocated to
CC       the nucleus.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed in fetal and adult
CC       tissues.
CC   -!- DOMAIN: The EGF-like domains 10 and 11 are required for binding
CC       the ligands JAG1 and DLL1. {ECO:0000269|PubMed:15350543}.
CC   -!- PTM: Synthesized in the endoplasmic reticulum as an inactive form
CC       which is proteolytically cleaved by a furin-like convertase in the
CC       trans-Golgi network before it reaches the plasma membrane to yield
CC       an active, ligand-accessible form. Cleavage results in a C-
CC       terminal fragment N(TM) and a N-terminal fragment N(EC). Following
CC       ligand binding, it is cleaved by TNF-alpha converting enzyme
CC       (TACE) to yield a membrane-associated intermediate fragment called
CC       notch extracellular truncation (NEXT). This fragment is then
CC       cleaved by presenilin dependent gamma-secretase to release a
CC       notch-derived peptide containing the intracellular domain (NICD)
CC       from the membrane. {ECO:0000269|PubMed:15350543}.
CC   -!- PTM: Phosphorylated. {ECO:0000250}.
CC   -!- PTM: Hydroxylated by HIF1AN. {ECO:0000269|PubMed:18299578}.
CC   -!- DISEASE: Cerebral arteriopathy, autosomal dominant, with
CC       subcortical infarcts and leukoencephalopathy, 1 (CADASIL1)
CC       [MIM:125310]: A cerebrovascular disease characterized by multiple
CC       subcortical infarcts, pseudobulbar palsy, dementia, and the
CC       presence of granular deposits in small cerebral arteries producing
CC       ischemic stroke. {ECO:0000269|PubMed:10227618,
CC       ECO:0000269|PubMed:10371548, ECO:0000269|PubMed:10802807,
CC       ECO:0000269|PubMed:10854111, ECO:0000269|PubMed:11058919,
CC       ECO:0000269|PubMed:11102981, ECO:0000269|PubMed:11559313,
CC       ECO:0000269|PubMed:11755616, ECO:0000269|PubMed:11810186,
CC       ECO:0000269|PubMed:12136071, ECO:0000269|PubMed:12146805,
CC       ECO:0000269|PubMed:12589106, ECO:0000269|PubMed:12810003,
CC       ECO:0000269|PubMed:15229130, ECO:0000269|PubMed:15300988,
CC       ECO:0000269|PubMed:15350543, ECO:0000269|PubMed:15364702,
CC       ECO:0000269|PubMed:15378071, ECO:0000269|PubMed:15818833,
CC       ECO:0000269|PubMed:16009764, ECO:0000269|PubMed:24000151,
CC       ECO:0000269|PubMed:9388399}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Myofibromatosis, infantile 2 (IMF2) [MIM:615293]: A rare
CC       mesenchymal disorder characterized by the development of benign
CC       tumors in the skin, striated muscles, bones, and, more rarely,
CC       visceral organs. Subcutaneous or soft tissue nodules commonly
CC       involve the skin of the head, neck, and trunk. Skeletal and
CC       muscular lesions occur in about half of the patients. Lesions may
CC       be solitary or multicentric, and they may be present at birth or
CC       become apparent in early infancy or occasionally in adult life.
CC       Visceral lesions are associated with high morbidity and mortality.
CC       {ECO:0000269|PubMed:23731542}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Lateral meningocele syndrome (LMNS) [MIM:130720]: A very
CC       rare skeletal disorder with facial anomalies, hypotonia and
CC       neurologic dysfunction due to meningocele, a protrusion of the
CC       meninges, unaccompanied by neural tissue, through a bony defect in
CC       the skull or vertebral column. LMNS facial features include
CC       hypertelorism and telecanthus, high arched eyebrows, ptosis, mid-
CC       facial hypoplasia, micrognathia, high and narrow palate, low-set
CC       ears and a hypotonic appearance. Additional variable features are
CC       connective tissue abnormalities, aortic dilation, a high-pitched
CC       nasal voice, wormian bones and osteolysis.
CC       {ECO:0000269|PubMed:25394726}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the NOTCH family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/NOTCH3ID41557ch19p13.html";
DR   EMBL; U97669; AAB91371.1; -; mRNA.
DR   EMBL; AF058900; AAC14346.1; -; Genomic_DNA.
DR   EMBL; AF058881; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058882; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058883; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058884; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058885; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058886; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058887; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058888; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058889; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058890; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058891; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058892; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058893; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058894; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058895; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058896; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058897; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058898; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AF058899; AAC14346.1; JOINED; Genomic_DNA.
DR   EMBL; AC004257; AAC04897.1; -; Genomic_DNA.
DR   EMBL; AC004663; AAC15789.1; -; Genomic_DNA.
DR   CCDS; CCDS12326.1; -.
DR   PIR; S78549; S78549.
DR   RefSeq; NP_000426.2; NM_000435.2.
DR   UniGene; Hs.8546; -.
DR   PDB; 4ZLP; X-ray; 2.48 A; A/B=1378-1640.
DR   PDB; 5CZV; X-ray; 3.19 A; A=1378-1640.
DR   PDB; 5CZX; X-ray; 2.10 A; A/B=1378-1640.
DR   PDBsum; 4ZLP; -.
DR   PDBsum; 5CZV; -.
DR   PDBsum; 5CZX; -.
DR   ProteinModelPortal; Q9UM47; -.
DR   SMR; Q9UM47; -.
DR   BioGrid; 110916; 67.
DR   DIP; DIP-39827N; -.
DR   ELM; Q9UM47; -.
DR   IntAct; Q9UM47; 20.
DR   MINT; Q9UM47; -.
DR   STRING; 9606.ENSP00000263388; -.
DR   BindingDB; Q9UM47; -.
DR   ChEMBL; CHEMBL3407319; -.
DR   GuidetoPHARMACOLOGY; 2860; -.
DR   iPTMnet; Q9UM47; -.
DR   PhosphoSitePlus; Q9UM47; -.
DR   BioMuta; NOTCH3; -.
DR   DMDM; 322510053; -.
DR   EPD; Q9UM47; -.
DR   jPOST; Q9UM47; -.
DR   MaxQB; Q9UM47; -.
DR   PaxDb; Q9UM47; -.
DR   PeptideAtlas; Q9UM47; -.
DR   PRIDE; Q9UM47; -.
DR   ProteomicsDB; 85176; -.
DR   Ensembl; ENST00000263388; ENSP00000263388; ENSG00000074181.
DR   GeneID; 4854; -.
DR   KEGG; hsa:4854; -.
DR   UCSC; uc002nan.4; human.
DR   CTD; 4854; -.
DR   DisGeNET; 4854; -.
DR   EuPathDB; HostDB:ENSG00000074181.8; -.
DR   GeneCards; NOTCH3; -.
DR   GeneReviews; NOTCH3; -.
DR   H-InvDB; HIX0040142; -.
DR   H-InvDB; HIX0174419; -.
DR   HGNC; HGNC:7883; NOTCH3.
DR   HPA; CAB005393; -.
DR   HPA; HPA044392; -.
DR   MalaCards; NOTCH3; -.
DR   MIM; 125310; phenotype.
DR   MIM; 130720; phenotype.
DR   MIM; 600276; gene.
DR   MIM; 615293; phenotype.
DR   neXtProt; NX_Q9UM47; -.
DR   OpenTargets; ENSG00000074181; -.
DR   Orphanet; 136; CADASIL.
DR   Orphanet; 2591; Infantile myofibromatosis.
DR   Orphanet; 2789; Lateral meningocele syndrome.
DR   PharmGKB; PA31685; -.
DR   eggNOG; ENOG410IR7G; Eukaryota.
DR   eggNOG; COG0666; LUCA.
DR   GeneTree; ENSGT00940000160234; -.
DR   HOGENOM; HOG000234369; -.
DR   HOVERGEN; HBG052650; -.
DR   InParanoid; Q9UM47; -.
DR   KO; K20995; -.
DR   OMA; LVGHYIC; -.
DR   OrthoDB; 606683at2759; -.
DR   PhylomeDB; Q9UM47; -.
DR   TreeFam; TF351641; -.
DR   Reactome; R-HSA-1912399; Pre-NOTCH Processing in the Endoplasmic Reticulum.
DR   Reactome; R-HSA-1912408; Pre-NOTCH Transcription and Translation.
DR   Reactome; R-HSA-1912420; Pre-NOTCH Processing in Golgi.
DR   Reactome; R-HSA-350054; Notch-HLH transcription pathway.
DR   Reactome; R-HSA-5083630; Defective LFNG causes SCDO3.
DR   Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR   Reactome; R-HSA-9013508; NOTCH3 Intracellular Domain Regulates Transcription.
DR   Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3.
DR   SignaLink; Q9UM47; -.
DR   SIGNOR; Q9UM47; -.
DR   ChiTaRS; NOTCH3; human.
DR   GeneWiki; Notch_3; -.
DR   GenomeRNAi; 4854; -.
DR   PRO; PR:Q9UM47; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   Bgee; ENSG00000074181; Expressed in 219 organ(s), highest expression level in vagina.
DR   ExpressionAtlas; Q9UM47; baseline and differential.
DR   Genevisible; Q9UM47; HS.
DR   GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0043235; C:receptor complex; IDA:MGI.
DR   GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0019899; F:enzyme binding; IEA:Ensembl.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0038023; F:signaling receptor activity; IMP:UniProtKB.
DR   GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl.
DR   GO; GO:0030900; P:forebrain development; IEA:Ensembl.
DR   GO; GO:0072104; P:glomerular capillary formation; IEA:Ensembl.
DR   GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR   GO; GO:0045746; P:negative regulation of Notch signaling pathway; TAS:Reactome.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0048663; P:neuron fate commitment; IEA:Ensembl.
DR   GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR   GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR   GO; GO:0007221; P:positive regulation of transcription of Notch receptor target; TAS:Reactome.
DR   GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR   CDD; cd00204; ANK; 2.
DR   Gene3D; 1.25.40.20; -; 1.
DR   InterPro; IPR002110; Ankyrin_rpt.
DR   InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR   InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR   InterPro; IPR024600; DUF3454_notch.
DR   InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR   InterPro; IPR013032; EGF-like_CS.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR   InterPro; IPR018097; EGF_Ca-bd_CS.
DR   InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR   InterPro; IPR008297; Notch.
DR   InterPro; IPR035993; Notch-like_dom_sf.
DR   InterPro; IPR022331; Notch_3.
DR   InterPro; IPR000800; Notch_dom.
DR   InterPro; IPR010660; Notch_NOD_dom.
DR   InterPro; IPR011656; Notch_NODP_dom.
DR   Pfam; PF12796; Ank_2; 2.
DR   Pfam; PF11936; DUF3454; 1.
DR   Pfam; PF00008; EGF; 19.
DR   Pfam; PF07645; EGF_CA; 5.
DR   Pfam; PF12661; hEGF; 3.
DR   Pfam; PF06816; NOD; 1.
DR   Pfam; PF07684; NODP; 1.
DR   Pfam; PF00066; Notch; 3.
DR   PIRSF; PIRSF002279; Notch; 1.
DR   PRINTS; PR01452; LNOTCHREPEAT.
DR   PRINTS; PR01986; NOTCH3.
DR   SMART; SM00248; ANK; 6.
DR   SMART; SM01334; DUF3454; 1.
DR   SMART; SM00181; EGF; 34.
DR   SMART; SM00179; EGF_CA; 31.
DR   SMART; SM00004; NL; 3.
DR   SMART; SM01338; NOD; 1.
DR   SMART; SM01339; NODP; 1.
DR   SUPFAM; SSF48403; SSF48403; 1.
DR   SUPFAM; SSF57184; SSF57184; 4.
DR   SUPFAM; SSF90193; SSF90193; 3.
DR   PROSITE; PS50297; ANK_REP_REGION; 1.
DR   PROSITE; PS50088; ANK_REPEAT; 4.
DR   PROSITE; PS00010; ASX_HYDROXYL; 18.
DR   PROSITE; PS00022; EGF_1; 33.
DR   PROSITE; PS01186; EGF_2; 25.
DR   PROSITE; PS50026; EGF_3; 34.
DR   PROSITE; PS01187; EGF_CA; 16.
DR   PROSITE; PS50258; LNR; 3.
PE   1: Evidence at protein level;
KW   3D-structure; Activator; ANK repeat; Cell membrane; Complete proteome;
KW   Developmental protein; Differentiation; Disease mutation;
KW   Disulfide bond; EGF-like domain; Glycoprotein; Membrane; Methylation;
KW   Notch signaling pathway; Nucleus; Phosphoprotein; Polymorphism;
KW   Receptor; Reference proteome; Repeat; Signal; Transcription;
KW   Transcription regulation; Transmembrane; Transmembrane helix.
FT   SIGNAL        1     39       {ECO:0000255}.
FT   CHAIN        40   2321       Neurogenic locus notch homolog protein 3.
FT                                /FTId=PRO_0000007692.
FT   CHAIN      1629   2321       Notch 3 extracellular truncation.
FT                                {ECO:0000250}.
FT                                /FTId=PRO_0000007693.
FT   CHAIN      1662   2321       Notch 3 intracellular domain.
FT                                {ECO:0000250}.
FT                                /FTId=PRO_0000007694.
FT   TOPO_DOM     40   1643       Extracellular. {ECO:0000255}.
FT   TRANSMEM   1644   1664       Helical. {ECO:0000255}.
FT   TOPO_DOM   1665   2321       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN       40     77       EGF-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN       78    118       EGF-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      119    156       EGF-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      158    195       EGF-like 4; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      197    234       EGF-like 5. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      236    272       EGF-like 6; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      274    312       EGF-like 7. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      314    350       EGF-like 8; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      351    389       EGF-like 9. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      391    429       EGF-like 10; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      431    467       EGF-like 11; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      469    505       EGF-like 12; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      507    543       EGF-like 13; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      545    580       EGF-like 14; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      582    618       EGF-like 15; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      620    655       EGF-like 16; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      657    693       EGF-like 17; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      695    730       EGF-like 18. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      734    770       EGF-like 19. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      771    808       EGF-like 20. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      810    847       EGF-like 21; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      849    885       EGF-like 22; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      887    922       EGF-like 23; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      924    960       EGF-like 24. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      962    998       EGF-like 25. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1000   1034       EGF-like 26. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1047   1082       EGF-like 27. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1084   1120       EGF-like 28. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1122   1158       EGF-like 29; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1160   1203       EGF-like 30; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1205   1244       EGF-like 31. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1246   1287       EGF-like 32. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1289   1325       EGF-like 33. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1335   1373       EGF-like 34. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   REPEAT     1387   1427       LNR 1.
FT   REPEAT     1428   1458       LNR 2.
FT   REPEAT     1467   1505       LNR 3.
FT   REPEAT     1838   1867       ANK 1.
FT   REPEAT     1871   1901       ANK 2.
FT   REPEAT     1905   1934       ANK 3.
FT   REPEAT     1938   1967       ANK 4.
FT   REPEAT     1971   2000       ANK 5.
FT   SITE       1571   1572       Cleavage; by furin-like protease.
FT                                {ECO:0000250}.
FT   MOD_RES    2174   2174       Omega-N-methylarginine.
FT                                {ECO:0000244|PubMed:24129315}.
FT   CARBOHYD   1179   1179       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1336   1336       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1438   1438       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID     43     55       {ECO:0000250}.
FT   DISULFID     49     65       {ECO:0000250}.
FT   DISULFID     67     76       {ECO:0000250}.
FT   DISULFID     82     93       {ECO:0000250}.
FT   DISULFID     87    106       {ECO:0000250}.
FT   DISULFID    108    117       {ECO:0000250}.
FT   DISULFID    123    134       {ECO:0000250}.
FT   DISULFID    128    144       {ECO:0000250}.
FT   DISULFID    146    155       {ECO:0000250}.
FT   DISULFID    162    174       {ECO:0000250}.
FT   DISULFID    168    183       {ECO:0000250}.
FT   DISULFID    185    194       {ECO:0000250}.
FT   DISULFID    201    212       {ECO:0000250}.
FT   DISULFID    206    222       {ECO:0000250}.
FT   DISULFID    224    233       {ECO:0000250}.
FT   DISULFID    240    251       {ECO:0000250}.
FT   DISULFID    245    260       {ECO:0000250}.
FT   DISULFID    262    271       {ECO:0000250}.
FT   DISULFID    278    291       {ECO:0000250}.
FT   DISULFID    285    300       {ECO:0000250}.
FT   DISULFID    302    311       {ECO:0000250}.
FT   DISULFID    318    329       {ECO:0000250}.
FT   DISULFID    323    338       {ECO:0000250}.
FT   DISULFID    340    349       {ECO:0000250}.
FT   DISULFID    355    366       {ECO:0000250}.
FT   DISULFID    360    377       {ECO:0000250}.
FT   DISULFID    379    388       {ECO:0000250}.
FT   DISULFID    395    408       {ECO:0000250}.
FT   DISULFID    402    417       {ECO:0000250}.
FT   DISULFID    419    428       {ECO:0000250}.
FT   DISULFID    435    446       {ECO:0000250}.
FT   DISULFID    440    455       {ECO:0000250}.
FT   DISULFID    457    466       {ECO:0000250}.
FT   DISULFID    473    484       {ECO:0000250}.
FT   DISULFID    478    493       {ECO:0000250}.
FT   DISULFID    495    504       {ECO:0000250}.
FT   DISULFID    511    522       {ECO:0000250}.
FT   DISULFID    516    531       {ECO:0000250}.
FT   DISULFID    533    542       {ECO:0000250}.
FT   DISULFID    549    559       {ECO:0000250}.
FT   DISULFID    554    568       {ECO:0000250}.
FT   DISULFID    570    579       {ECO:0000250}.
FT   DISULFID    586    597       {ECO:0000250}.
FT   DISULFID    591    606       {ECO:0000250}.
FT   DISULFID    608    617       {ECO:0000250}.
FT   DISULFID    624    634       {ECO:0000250}.
FT   DISULFID    629    643       {ECO:0000250}.
FT   DISULFID    645    654       {ECO:0000250}.
FT   DISULFID    661    672       {ECO:0000250}.
FT   DISULFID    666    681       {ECO:0000250}.
FT   DISULFID    683    692       {ECO:0000250}.
FT   DISULFID    699    709       {ECO:0000250}.
FT   DISULFID    704    718       {ECO:0000250}.
FT   DISULFID    720    729       {ECO:0000250}.
FT   DISULFID    738    749       {ECO:0000250}.
FT   DISULFID    743    758       {ECO:0000250}.
FT   DISULFID    760    769       {ECO:0000250}.
FT   DISULFID    775    786       {ECO:0000250}.
FT   DISULFID    780    796       {ECO:0000250}.
FT   DISULFID    798    807       {ECO:0000250}.
FT   DISULFID    814    826       {ECO:0000250}.
FT   DISULFID    820    835       {ECO:0000250}.
FT   DISULFID    837    846       {ECO:0000250}.
FT   DISULFID    853    864       {ECO:0000250}.
FT   DISULFID    858    873       {ECO:0000250}.
FT   DISULFID    875    884       {ECO:0000250}.
FT   DISULFID    891    901       {ECO:0000250}.
FT   DISULFID    896    910       {ECO:0000250}.
FT   DISULFID    912    921       {ECO:0000250}.
FT   DISULFID    928    939       {ECO:0000250}.
FT   DISULFID    933    948       {ECO:0000250}.
FT   DISULFID    950    959       {ECO:0000250}.
FT   DISULFID    966    977       {ECO:0000250}.
FT   DISULFID    971    986       {ECO:0000250}.
FT   DISULFID    988    997       {ECO:0000250}.
FT   DISULFID   1004   1015       {ECO:0000250}.
FT   DISULFID   1009   1022       {ECO:0000250}.
FT   DISULFID   1024   1033       {ECO:0000250}.
FT   DISULFID   1040   1061       {ECO:0000250}.
FT   DISULFID   1055   1070       {ECO:0000250}.
FT   DISULFID   1072   1081       {ECO:0000250}.
FT   DISULFID   1088   1099       {ECO:0000250}.
FT   DISULFID   1093   1108       {ECO:0000250}.
FT   DISULFID   1110   1119       {ECO:0000250}.
FT   DISULFID   1126   1137       {ECO:0000250}.
FT   DISULFID   1131   1146       {ECO:0000250}.
FT   DISULFID   1148   1157       {ECO:0000250}.
FT   DISULFID   1164   1182       {ECO:0000250}.
FT   DISULFID   1176   1191       {ECO:0000250}.
FT   DISULFID   1193   1202       {ECO:0000250}.
FT   DISULFID   1209   1222       {ECO:0000250}.
FT   DISULFID   1214   1232       {ECO:0000250}.
FT   DISULFID   1234   1243       {ECO:0000250}.
FT   DISULFID   1250   1261       {ECO:0000250}.
FT   DISULFID   1255   1275       {ECO:0000250}.
FT   DISULFID   1277   1286       {ECO:0000250}.
FT   DISULFID   1293   1304       {ECO:0000250}.
FT   DISULFID   1298   1313       {ECO:0000250}.
FT   DISULFID   1315   1324       {ECO:0000250}.
FT   DISULFID   1339   1350       {ECO:0000250}.
FT   DISULFID   1344   1361       {ECO:0000250}.
FT   DISULFID   1363   1372       {ECO:0000250}.
FT   DISULFID   1387   1410       {ECO:0000250}.
FT   DISULFID   1392   1405       {ECO:0000250}.
FT   DISULFID   1401   1417       {ECO:0000250}.
FT   DISULFID   1428   1451       {ECO:0000250}.
FT   DISULFID   1433   1446       {ECO:0000250}.
FT   DISULFID   1442   1458       {ECO:0000250}.
FT   DISULFID   1467   1493       {ECO:0000250}.
FT   DISULFID   1475   1488       {ECO:0000250}.
FT   DISULFID   1484   1500       {ECO:0000250}.
FT   VARIANT      43     43       C -> G (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044230.
FT   VARIANT      49     49       C -> F (in CADASIL1; dbSNP:rs193921045).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044231.
FT   VARIANT      49     49       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012871.
FT   VARIANT      54     54       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044232.
FT   VARIANT      60     60       S -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044233.
FT   VARIANT      65     65       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044234.
FT   VARIANT      67     67       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:12589106}.
FT                                /FTId=VAR_044235.
FT   VARIANT      71     71       W -> C (in CADASIL1; dbSNP:rs28937321).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012872.
FT   VARIANT      76     76       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805,
FT                                ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044236.
FT   VARIANT      76     76       C -> W (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044237.
FT   VARIANT      77     82       Missing (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044238.
FT   VARIANT      80     84       Missing (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044239.
FT   VARIANT      87     87       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044240.
FT   VARIANT      87     87       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044241.
FT   VARIANT      90     90       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:12810003,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012873.
FT   VARIANT      93     93       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044242.
FT   VARIANT      93     93       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044243.
FT   VARIANT     106    106       C -> W (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044244.
FT   VARIANT     108    108       C -> W (in CADASIL1).
FT                                {ECO:0000269|PubMed:15300988}.
FT                                /FTId=VAR_044245.
FT   VARIANT     108    108       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044246.
FT   VARIANT     110    110       R -> C (in CADASIL1; dbSNP:rs775836288).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012874.
FT   VARIANT     114    120       Missing (in CADASIL1).
FT                                {ECO:0000269|PubMed:10802807,
FT                                ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_012875.
FT   VARIANT     117    117       C -> F (in CADASIL1; dbSNP:rs773539041).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044247.
FT   VARIANT     118    118       S -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15818833}.
FT                                /FTId=VAR_044248.
FT   VARIANT     123    123       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044249.
FT   VARIANT     123    123       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044250.
FT   VARIANT     128    128       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044251.
FT   VARIANT     133    133       R -> C (in CADASIL1; no effect on ligand-
FT                                binding; no effect on cell membrane
FT                                localization; reduced proteolytic
FT                                processing; dbSNP:rs137852642).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10371548,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:12810003,
FT                                ECO:0000269|PubMed:15350543,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:15378071,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012876.
FT   VARIANT     134    134       C -> W (in CADASIL1).
FT                                {ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:11810186,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044252.
FT   VARIANT     141    141       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10371548,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012877.
FT   VARIANT     142    142       F -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044253.
FT   VARIANT     144    144       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:11058919}.
FT                                /FTId=VAR_044254.
FT   VARIANT     144    144       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044255.
FT   VARIANT     144    144       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044256.
FT   VARIANT     145    145       S -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044257.
FT   VARIANT     146    146       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012878.
FT   VARIANT     149    149       G -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044258.
FT   VARIANT     150    150       Y -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044259.
FT   VARIANT     153    155       Missing (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044260.
FT   VARIANT     153    153       R -> C (in CADASIL1; dbSNP:rs797045014).
FT                                {ECO:0000269|PubMed:10371548,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012879.
FT   VARIANT     155    155       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044261.
FT   VARIANT     162    162       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044262.
FT   VARIANT     169    169       R -> C (in CADASIL1; dbSNP:rs28933696).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:12810003,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012880.
FT   VARIANT     170    170       H -> R (in dbSNP:rs147373451).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012881.
FT   VARIANT     171    171       G -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012882.
FT   VARIANT     174    174       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:12810003}.
FT                                /FTId=VAR_044263.
FT   VARIANT     174    174       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:12810003,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044264.
FT   VARIANT     174    174       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044265.
FT   VARIANT     180    180       S -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044266.
FT   VARIANT     182    182       R -> C (in CADASIL1; dbSNP:rs28933697).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10371548,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012883.
FT   VARIANT     183    183       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044267.
FT   VARIANT     183    183       C -> R (in CADASIL1; no effect on ligand-
FT                                binding; no effect on cell membrane
FT                                localization; reduced proteolytic
FT                                processing).
FT                                {ECO:0000269|PubMed:10227618,
FT                                ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15350543,
FT                                ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044268.
FT   VARIANT     183    183       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044269.
FT   VARIANT     185    185       C -> G (in CADASIL1).
FT                                {ECO:0000269|PubMed:11755616}.
FT                                /FTId=VAR_044270.
FT   VARIANT     185    185       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012884.
FT   VARIANT     189    189       Y -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044271.
FT   VARIANT     194    194       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:10854111,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044272.
FT   VARIANT     194    194       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044273.
FT   VARIANT     194    194       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044274.
FT   VARIANT     194    194       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044275.
FT   VARIANT     201    201       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044276.
FT   VARIANT     206    206       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044277.
FT   VARIANT     207    207       R -> C (in CADASIL1; dbSNP:rs775267348).
FT                                {ECO:0000269|PubMed:10371548,
FT                                ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044278.
FT   VARIANT     212    212       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012885.
FT   VARIANT     213    213       R -> K (in CADASIL1).
FT                                {ECO:0000269|PubMed:12810003}.
FT                                /FTId=VAR_044279.
FT   VARIANT     222    222       C -> G (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012886.
FT   VARIANT     222    222       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044280.
FT   VARIANT     224    224       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012887.
FT   VARIANT     233    233       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044281.
FT   VARIANT     233    233       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044282.
FT   VARIANT     239    253       Missing (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044283.
FT   VARIANT     240    240       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044284.
FT   VARIANT     245    245       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044285.
FT   VARIANT     251    251       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805,
FT                                ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044286.
FT   VARIANT     258    258       Y -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012888.
FT   VARIANT     260    260       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044287.
FT   VARIANT     319    319       A -> C (in CADASIL1; requires 2
FT                                nucleotide substitutions).
FT                                {ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044288.
FT   VARIANT     332    332       R -> C (in CADASIL1; dbSNP:rs137852641).
FT                                {ECO:0000269|PubMed:11559313,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044289.
FT   VARIANT     335    335       S -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044290.
FT   VARIANT     337    337       Y -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044291.
FT   VARIANT     379    379       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044292.
FT   VARIANT     395    395       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044293.
FT   VARIANT     420    420       G -> C (in CADASIL1; dbSNP:rs1323608032).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044294.
FT   VARIANT     421    421       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044295.
FT   VARIANT     428    428       C -> S (in CADASIL1; dbSNP:rs267606915).
FT                                {ECO:0000269|PubMed:11755616}.
FT                                /FTId=VAR_044296.
FT   VARIANT     428    428       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044297.
FT   VARIANT     440    440       C -> G (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805,
FT                                ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044298.
FT   VARIANT     440    440       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044299.
FT   VARIANT     446    446       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044300.
FT   VARIANT     449    449       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044301.
FT   VARIANT     455    455       C -> R (in CADASIL1; impaired ligand-
FT                                binding; strongly reduced signaling
FT                                activity; no effect on cell membrane
FT                                localization; reduced proteolytic
FT                                processing; dbSNP:rs28933698).
FT                                {ECO:0000269|PubMed:12136071,
FT                                ECO:0000269|PubMed:15350543}.
FT                                /FTId=VAR_044302.
FT   VARIANT     484    484       C -> F (in CADASIL1).
FT                                {ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044303.
FT   VARIANT     484    484       C -> Y (in CADASIL1; dbSNP:rs1313319587).
FT                                {ECO:0000269|PubMed:15364702}.
FT                                /FTId=VAR_044304.
FT   VARIANT     495    495       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044305.
FT   VARIANT     496    496       P -> L (in dbSNP:rs11670799).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012889.
FT   VARIANT     511    511       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044306.
FT   VARIANT     542    542       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012890.
FT   VARIANT     544    544       R -> C (in CADASIL1; dbSNP:rs201118034).
FT                                {ECO:0000269|PubMed:10371548}.
FT                                /FTId=VAR_044307.
FT   VARIANT     549    549       C -> Y (in CADASIL1).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044308.
FT   VARIANT     558    558       R -> C (in CADASIL1; dbSNP:rs75068032).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012891.
FT   VARIANT     578    578       R -> C (in CADASIL1; dbSNP:rs769773673).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012892.
FT   VARIANT     607    607       R -> C (in CADASIL1; dbSNP:rs777751303).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044309.
FT   VARIANT     710    710       Y -> C (in CADASIL1; found in a compound
FT                                heterozygote also carrying an intragenic
FT                                frameshift deletion; dbSNP:rs1328784046).
FT                                {ECO:0000269|PubMed:24000151}.
FT                                /FTId=VAR_072080.
FT   VARIANT     728    728       R -> C (in CADASIL1; dbSNP:rs1057519101).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012893.
FT   VARIANT     775    775       C -> S (in CADASIL1).
FT                                {ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044310.
FT   VARIANT     953    953       G -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:12146805,
FT                                ECO:0000269|PubMed:15229130}.
FT                                /FTId=VAR_044311.
FT   VARIANT     984    984       F -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981}.
FT                                /FTId=VAR_044312.
FT   VARIANT     985    985       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:11755616,
FT                                ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012894.
FT   VARIANT    1006   1006       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012895.
FT   VARIANT    1015   1015       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:10371548}.
FT                                /FTId=VAR_044313.
FT   VARIANT    1020   1020       A -> P (in dbSNP:rs35769976).
FT                                /FTId=VAR_044314.
FT   VARIANT    1021   1021       Y -> C (in CADASIL1; dbSNP:rs1167405466).
FT                                {ECO:0000269|PubMed:12146805}.
FT                                /FTId=VAR_044315.
FT   VARIANT    1031   1031       R -> C (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012896.
FT   VARIANT    1063   1063       D -> C (in CADASIL1; requires 2
FT                                nucleotide substitutions).
FT                                {ECO:0000269|PubMed:11755616}.
FT                                /FTId=VAR_044316.
FT   VARIANT    1133   1133       H -> Q (in dbSNP:rs112197217).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012897.
FT   VARIANT    1183   1183       V -> M (in dbSNP:rs10408676).
FT                                {ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012898.
FT   VARIANT    1231   1231       R -> C (in CADASIL1; dbSNP:rs201680145).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:15229130,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012899.
FT   VARIANT    1261   1261       C -> R (in CADASIL1).
FT                                {ECO:0000269|PubMed:11102981,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012900.
FT   VARIANT    1261   1261       C -> Y (in CADASIL1; dbSNP:rs1209610920).
FT                                {ECO:0000269|PubMed:15364702,
FT                                ECO:0000269|PubMed:16009764}.
FT                                /FTId=VAR_044317.
FT   VARIANT    1515   1515       L -> P (in brain small-vessel-disease;
FT                                exhibits increased NOTCH3 signaling in a
FT                                ligand-independent fashion).
FT                                {ECO:0000269|PubMed:18273901}.
FT                                /FTId=VAR_044318.
FT   VARIANT    1519   1519       L -> P (in IMF2; dbSNP:rs367543285).
FT                                {ECO:0000269|PubMed:23731542}.
FT                                /FTId=VAR_069927.
FT   VARIANT    2223   2223       A -> V (in dbSNP:rs1044009).
FT                                {ECO:0000269|PubMed:8878478,
FT                                ECO:0000269|PubMed:9388399}.
FT                                /FTId=VAR_012901.
FT   STRAND     1389   1391       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1393   1395       {ECO:0000244|PDB:5CZV}.
FT   STRAND     1398   1400       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1403   1405       {ECO:0000244|PDB:4ZLP}.
FT   TURN       1408   1410       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1411   1414       {ECO:0000244|PDB:5CZX}.
FT   TURN       1415   1420       {ECO:0000244|PDB:5CZX}.
FT   TURN       1424   1427       {ECO:0000244|PDB:5CZX}.
FT   TURN       1431   1433       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1434   1437       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1439   1441       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1444   1446       {ECO:0000244|PDB:5CZX}.
FT   TURN       1449   1451       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1452   1456       {ECO:0000244|PDB:5CZX}.
FT   TURN       1457   1459       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1463   1465       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1469   1471       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1472   1478       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1481   1483       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1486   1488       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1491   1493       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1495   1498       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1510   1519       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1521   1526       {ECO:0000244|PDB:5CZX}.
FT   HELIX      1528   1539       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1541   1545       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1555   1558       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1579   1587       {ECO:0000244|PDB:5CZX}.
FT   TURN       1589   1592       {ECO:0000244|PDB:5CZV}.
FT   TURN       1595   1597       {ECO:0000244|PDB:4ZLP}.
FT   STRAND     1598   1600       {ECO:0000244|PDB:5CZV}.
FT   HELIX      1604   1616       {ECO:0000244|PDB:5CZX}.
FT   STRAND     1626   1632       {ECO:0000244|PDB:5CZX}.
SQ   SEQUENCE   2321 AA;  243631 MW;  3E70EC12A59CD638 CRC64;
     MGPGARGRRR RRRPMSPPPP PPPVRALPLL LLLAGPGAAA PPCLDGSPCA NGGRCTQLPS
     REAACLCPPG WVGERCQLED PCHSGPCAGR GVCQSSVVAG TARFSCRCPR GFRGPDCSLP
     DPCLSSPCAH GARCSVGPDG RFLCSCPPGY QGRSCRSDVD ECRVGEPCRH GGTCLNTPGS
     FRCQCPAGYT GPLCENPAVP CAPSPCRNGG TCRQSGDLTY DCACLPGFEG QNCEVNVDDC
     PGHRCLNGGT CVDGVNTYNC QCPPEWTGQF CTEDVDECQL QPNACHNGGT CFNTLGGHSC
     VCVNGWTGES CSQNIDDCAT AVCFHGATCH DRVASFYCAC PMGKTGLLCH LDDACVSNPC
     HEDAICDTNP VNGRAICTCP PGFTGGACDQ DVDECSIGAN PCEHLGRCVN TQGSFLCQCG
     RGYTGPRCET DVNECLSGPC RNQATCLDRI GQFTCICMAG FTGTYCEVDI DECQSSPCVN
     GGVCKDRVNG FSCTCPSGFS GSTCQLDVDE CASTPCRNGA KCVDQPDGYE CRCAEGFEGT
     LCDRNVDDCS PDPCHHGRCV DGIASFSCAC APGYTGTRCE SQVDECRSQP CRHGGKCLDL
     VDKYLCRCPS GTTGVNCEVN IDDCASNPCT FGVCRDGINR YDCVCQPGFT GPLCNVEINE
     CASSPCGEGG SCVDGENGFR CLCPPGSLPP LCLPPSHPCA HEPCSHGICY DAPGGFRCVC
     EPGWSGPRCS QSLARDACES QPCRAGGTCS SDGMGFHCTC PPGVQGRQCE LLSPCTPNPC
     EHGGRCESAP GQLPVCSCPQ GWQGPRCQQD VDECAGPAPC GPHGICTNLA GSFSCTCHGG
     YTGPSCDQDI NDCDPNPCLN GGSCQDGVGS FSCSCLPGFA GPRCARDVDE CLSNPCGPGT
     CTDHVASFTC TCPPGYGGFH CEQDLPDCSP SSCFNGGTCV DGVNSFSCLC RPGYTGAHCQ
     HEADPCLSRP CLHGGVCSAA HPGFRCTCLE SFTGPQCQTL VDWCSRQPCQ NGGRCVQTGA
     YCLCPPGWSG RLCDIRSLPC REAAAQIGVR LEQLCQAGGQ CVDEDSSHYC VCPEGRTGSH
     CEQEVDPCLA QPCQHGGTCR GYMGGYMCEC LPGYNGDNCE DDVDECASQP CQHGGSCIDL
     VARYLCSCPP GTLGVLCEIN EDDCGPGPPL DSGPRCLHNG TCVDLVGGFR CTCPPGYTGL
     RCEADINECR SGACHAAHTR DCLQDPGGGF RCLCHAGFSG PRCQTVLSPC ESQPCQHGGQ
     CRPSPGPGGG LTFTCHCAQP FWGPRCERVA RSCRELQCPV GVPCQQTPRG PRCACPPGLS
     GPSCRSFPGS PPGASNASCA AAPCLHGGSC RPAPLAPFFR CACAQGWTGP RCEAPAAAPE
     VSEEPRCPRA ACQAKRGDQR CDRECNSPGC GWDGGDCSLS VGDPWRQCEA LQCWRLFNNS
     RCDPACSSPA CLYDNFDCHA GGRERTCNPV YEKYCADHFA DGRCDQGCNT EECGWDGLDC
     ASEVPALLAR GVLVLTVLLP PEELLRSSAD FLQRLSAILR TSLRFRLDAH GQAMVFPYHR
     PSPGSEPRAR RELAPEVIGS VVMLEIDNRL CLQSPENDHC FPDAQSAADY LGALSAVERL
     DFPYPLRDVR GEPLEPPEPS VPLLPLLVAG AVLLLVILVL GVMVARRKRE HSTLWFPEGF
     SLHKDVASGH KGRREPVGQD ALGMKNMAKG ESLMGEVATD WMDTECPEAK RLKVEEPGMG
     AEEAVDCRQW TQHHLVAADI RVAPAMALTP PQGDADADGM DVNVRGPDGF TPLMLASFCG
     GALEPMPTEE DEADDTSASI ISDLICQGAQ LGARTDRTGE TALHLAARYA RADAAKRLLD
     AGADTNAQDH SGRTPLHTAV TADAQGVFQI LIRNRSTDLD ARMADGSTAL ILAARLAVEG
     MVEELIASHA DVNAVDELGK SALHWAAAVN NVEATLALLK NGANKDMQDS KEETPLFLAA
     REGSYEAAKL LLDHFANREI TDHLDRLPRD VAQERLHQDI VRLLDQPSGP RSPPGPHGLG
     PLLCPPGAFL PGLKAAQSGS KKSRRPPGKA GLGPQGPRGR GKKLTLACPG PLADSSVTLS
     PVDSLDSPRP FGGPPASPGG FPLEGPYAAA TATAVSLAQL GGPGRAGLGR QPPGGCVLSL
     GLLNPVAVPL DWARLPPPAP PGPSFLLPLA PGPQLLNPGT PVSPQERPPP YLAVPGHGEE
     YPAAGAHSSP PKARFLRVPS EHPYLTPSPE SPEHWASPSP PSLSDWSEST PSPATATGAM
     ATTTGALPAQ PLPLSVPSSL AQAQTQLGPQ PEVTPKRQVL A
//
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