RBCC

Full text data of NCSTN

NCSTN (KIAA0253) [Confidence: high (present in two of the MS resources)]
Nicastrin; Flags: Precursor

hRBCD IPI00021983
IPI00021983 Splice isoform 1 of Q92542 Nicastrin precursor Splice isoform 1 of Q92542 Nicastrin precursor membrane n/a n/a 2 1 2 1 1 n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a 1 Type I membrane protein n/a found at its expected molecular weight found at molecular weight

Comments
Isoform Q92542-2 was detected.

UniProt Q92542
ID NICA_HUMAN Reviewed; 709 AA.
AC Q92542; Q5T207; Q5T208; Q86VV5;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2001, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Nicastrin;
DE Flags: Precursor;
GN Name=NCSTN; Synonyms=KIAA0253; ORFNames=UNQ1874/PRO4317;
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] (ISOFORM 1), AND MUTAGENESIS OF
RP 336-ASP-TYR-337.
RC TISSUE=Embryonic kidney;
RX PubMed=10993067; DOI=10.1038/35024009;
RA Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A.,
RA Song Y.-Q., Rogaeva E., Chen F., Kawarai T., Supala A., Levesque L.,
RA Yu H., Yang D.-S., Holmes E., Milman P., Liang Y., Zhang D.M.,
RA Xu D.H., Sato C., Rogaev E., Smith M., Janus C., Zhang Y.,
RA Aebersold R., Farrer L.S., Sorbi S., Bruni A., Fraser P.E.,
RA St George-Hyslop P.H.;
RT "Nicastrin modulates presenilin-mediated notch/glp-1 signal
RT transduction and betaAPP processing.";
RL Nature 407:48-54(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2-709 (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI.
RT The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by
RT analysis of cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [8]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=11396676; DOI=10.1046/j.1440-1789.2001.00378.x;
RA Satoh J., Kuroda Y.;
RT "Nicastrin, a key regulator of presenilin function, is expressed
RT constitutively in human neural cell lines.";
RL Neuropathology 21:115-122(2001).
RN [9]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [10]
RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND
RP APH1A.
RX PubMed=12740439; DOI=10.1073/pnas.1037392100;
RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S.,
RA Selkoe D.J.;
RT "Gamma-secretase is a membrane protein complex comprised of
RT presenilin, nicastrin, Aph-1, and Pen-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003).
RN [11]
RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX.
RX PubMed=12679784; DOI=10.1038/ncb960;
RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.;
RT "Reconstitution of gamma-secretase activity.";
RL Nat. Cell Biol. 5:486-488(2003).
RN [12]
RP GLYCOSYLATION AT ASN-387.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [13]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-45; ASN-187 AND ASN-387,
RP AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-612, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-
RT linked cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [16]
RP INVOLVEMENT IN ACNINV1.
RX PubMed=20929727; DOI=10.1126/science.1196284;
RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y.,
RA Qu T., Chen M., Sun M., Shen Y., Zhang X.;
RT "Gamma-secretase gene mutations in familial acne inversa.";
RL Science 330:1065-1065(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP INVOLVEMENT IN ACNINV1.
RX PubMed=21430701; DOI=10.1038/jid.2011.62;
RA Liu Y., Gao M., Lv Y.M., Yang X., Ren Y.Q., Jiang T., Zhang X.,
RA Guo B.R., Li M., Zhang Q., Zhang P., Zhou F.S., Chen G., Yin X.Y.,
RA Zuo X.B., Sun L.D., Zheng X.D., Zhang S.M., Liu J.J., Zhou Y.,
RA Li Y.R., Wang J., Wang J., Yang H.M., Yang S., Li R.Q., Zhang X.J.;
RT "Confirmation by exome sequencing of the pathogenic role of NCSTN
RT mutations in acne inversa (hidradenitis suppurativa).";
RL J. Invest. Dermatol. 131:1570-1572(2011).
RN [19]
RP VARIANT ACNINV1 ARG-211.
RX PubMed=21495993; DOI=10.1111/j.1365-2133.2011.10372.x;
RA Li C.R., Jiang M.J., Shen D.B., Xu H.X., Wang H.S., Yao X., Zhang Y.,
RA Zhou W.Q., Wang B.;
RT "Two novel mutations of the nicastrin gene in Chinese patients with
RT acne inversa.";
RL Br. J. Dermatol. 165:415-418(2011).
CC -!- FUNCTION: Essential subunit of the gamma-secretase complex, an
CC endoprotease complex that catalyzes the intramembrane cleavage of
CC integral membrane proteins such as Notch receptors and APP (beta-
CC amyloid precursor protein). It probably represents a stabilizing
CC cofactor required for the assembly of the gamma-secretase complex.
CC -!- SUBUNIT: Component of the gamma-secretase complex, a complex
CC composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin
CC (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is
CC sufficient for secretase activity, although other components may
CC exist. Binds to proteolytic processed C-terminal fragments C83 and
CC C99 of the amyloid precursor protein (APP).
CC -!- INTERACTION:
CC Q96BI3:APH1A; NbExp=3; IntAct=EBI-998440, EBI-2606935;
CC P49768:PSEN1; NbExp=3; IntAct=EBI-998440, EBI-297277;
CC Q9NZ42:PSENEN; NbExp=3; IntAct=EBI-998440, EBI-998468;
CC P49755:TMED10; NbExp=5; IntAct=EBI-998440, EBI-998422;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein (Potential). Melanosome. Note=Identified by mass
CC spectrometry in melanosome fractions from stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q92542-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92542-2; Sequence=VSP_008385, VSP_008386;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- INDUCTION: Constitutively expressed in neural cells.
CC -!- DISEASE: Acne inversa, familial, 1 (ACNINV1) [MIM:142690]: A
CC chronic relapsing inflammatory disease of the hair follicles
CC characterized by recurrent draining sinuses, painful skin
CC abscesses, and disfiguring scars. Manifestations typically appear
CC after puberty. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the nicastrin family.
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DR EMBL; AF240468; AAG11412.1; -; mRNA.
DR EMBL; AY359120; AAQ89478.1; -; mRNA.
DR EMBL; AK314764; BAG37302.1; -; mRNA.
DR EMBL; AL445230; CAI15009.1; -; Genomic_DNA.
DR EMBL; AL445230; CAI15010.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52720.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52721.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52722.1; -; Genomic_DNA.
DR EMBL; BC047621; AAH47621.1; -; mRNA.
DR EMBL; D87442; BAA13383.1; -; mRNA.
DR RefSeq; NP_056146.1; NM_015331.2.
DR RefSeq; XP_005245108.1; XM_005245051.1.
DR UniGene; Hs.517249; -.
DR ProteinModelPortal; Q92542; -.
DR DIP; DIP-36336N; -.
DR IntAct; Q92542; 12.
DR MINT; MINT-3048708; -.
DR STRING; 9606.ENSP00000294785; -.
DR BindingDB; Q92542; -.
DR ChEMBL; CHEMBL2094135; -.
DR PhosphoSite; Q92542; -.
DR DMDM; 12231037; -.
DR PaxDb; Q92542; -.
DR PRIDE; Q92542; -.
DR DNASU; 23385; -.
DR Ensembl; ENST00000294785; ENSP00000294785; ENSG00000162736.
DR Ensembl; ENST00000368063; ENSP00000357042; ENSG00000162736.
DR Ensembl; ENST00000392212; ENSP00000376047; ENSG00000162736.
DR GeneID; 23385; -.
DR KEGG; hsa:23385; -.
DR UCSC; uc001fvx.3; human.
DR CTD; 23385; -.
DR GeneCards; GC01P160313; -.
DR HGNC; HGNC:17091; NCSTN.
DR HPA; CAB021982; -.
DR MIM; 142690; phenotype.
DR MIM; 605254; gene.
DR neXtProt; NX_Q92542; -.
DR PharmGKB; PA142671271; -.
DR eggNOG; NOG253370; -.
DR HOGENOM; HOG000044212; -.
DR HOVERGEN; HBG006497; -.
DR InParanoid; Q92542; -.
DR KO; K06171; -.
DR OMA; HMHAVIS; -.
DR OrthoDB; EOG77WWCF; -.
DR PhylomeDB; Q92542; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_691; A third proteolytic cleavage releases NICD.
DR SignaLink; Q92542; -.
DR GeneWiki; Nicastrin; -.
DR GenomeRNAi; 23385; -.
DR NextBio; 45500; -.
DR PRO; PR:Q92542; -.
DR ArrayExpress; Q92542; -.
DR Bgee; Q92542; -.
DR CleanEx; HS_NCSTN; -.
DR Genevestigator; Q92542; -.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0004175; F:endopeptidase activity; IEA:Ensembl.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; TAS:HGNC.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0050435; P:beta-amyloid metabolic process; IEA:Ensembl.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; ISS:UniProtKB.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; TAS:Reactome.
DR GO; GO:0002262; P:myeloid cell homeostasis; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007220; P:Notch receptor processing; TAS:HGNC.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0043085; P:positive regulation of catalytic activity; ISS:UniProtKB.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:0042098; P:T cell proliferation; IEA:Ensembl.
DR InterPro; IPR008710; Nicastrin.
DR PANTHER; PTHR21092; PTHR21092; 1.
DR Pfam; PF05450; Nicastrin; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Glycoprotein; Membrane; Notch signaling pathway; Polymorphism;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 33 Potential.
FT CHAIN 34 709 Nicastrin.
FT /FTId=PRO_0000019681.
FT TOPO_DOM 34 669 Extracellular (Potential).
FT TRANSMEM 670 690 Helical; (Potential).
FT TOPO_DOM 691 709 Cytoplasmic (Potential).
FT CARBOHYD 45 45 N-linked (GlcNAc...).
FT CARBOHYD 55 55 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 187 187 N-linked (GlcNAc...).
FT CARBOHYD 200 200 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 204 204 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 264 264 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 387 387 N-linked (GlcNAc...).
FT CARBOHYD 417 417 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 435 435 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 464 464 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 506 506 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 530 530 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 562 562 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 573 573 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 580 580 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 612 612 N-linked (GlcNAc...).
FT VAR_SEQ 1 20 Missing (in isoform 2).
FT /FTId=VSP_008385.
FT VAR_SEQ 21 29 LSFCVLLAG -> MDFNLILES (in isoform 2).
FT /FTId=VSP_008386.
FT VARIANT 75 75 V -> I (in dbSNP:rs12045198).
FT /FTId=VAR_050274.
FT VARIANT 77 77 E -> D (in dbSNP:rs35603924).
FT /FTId=VAR_050275.
FT VARIANT 211 211 P -> R (in ACNINV1).
FT /FTId=VAR_067756.
FT MUTAGEN 336 337 DY->AA: Increases production of amyloid
FT beta (beta-APP40 and beta-APP42) in APP
FT processing.
FT CONFLICT 657 657 R -> H (in Ref. 6; AAH47621).
SQ SEQUENCE 709 AA; 78411 MW; C8C0EAEAD89E976A CRC64;
MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI
GCQSSISGDT GVIHVVEKEE DLQWVLTDGP NPPYMVLLES KHFTRDLMEK LKGRTSRIAG
LAVSLTKPSP ASGFSPSVQC PNDGFGVYSN SYGPEFAHCR EIQWNSLGNG LAYEDFSFPI
FLLEDENETK VIKQCYQDHN LSQNGSAPTF PLCAMQLFSH MHAVISTATC MRRSSIQSTF
SINPEIVCDP LSDYNVWSML KPINTTGTLK PDDRVVVAAT RLDSRSFFWN VAPGAESAVA
SFVTQLAAAE ALQKAPDVTT LPRNVMFVFF QGETFDYIGS SRMVYDMEKG KFPVQLENVD
SFVELGQVAL RTSLELWMHT DPVSQKNESV RNQVEDLLAT LEKSGAGVPA VILRRPNQSQ
PLPPSSLQRF LRARNISGVV LADHSGAFHN KYYQSIYDTA ENINVSYPEW LSPEEDLNFV
TDTAKALADV ATVLGRALYE LAGGTNFSDT VQADPQTVTR LLYGFLIKAN NSWFQSILRQ
DLRSYLGDGP LQHYIAVSSP TNTTYVVQYA LANLTGTVVN LTREQCQDPS KVPSENKDLY
EYSWVQGPLH SNETDRLPRC VRSTARLARA LSPAFELSQW SSTEYSTWTE SRWKDIRARI
FLIASKELEL ITLTVGFGIL IFSLIVTYCI NAKADVLFIA PREPGAVSY
//

MIM 142690
*RECORD*
*FIELD* NO
142690
*FIELD* TI
#142690 ACNE INVERSA, FAMILIAL, 1; ACNINV1
;;ACNE INVERSA, FAMILIAL;;
HIDRADENITIS SUPPURATIVA, FAMILIAL
read more*FIELD* TX
A number sign (#) is used with this entry because familial acne
inversa-1 (ACNINV1) is caused by haploinsufficiency for the gene
encoding nicastrin (NCSTN; 605254) on chromosome 1q22-q23.

DESCRIPTION

Acne inversa is a chronic relapsing inflammatory skin disease
characterized by recurrent draining sinuses and abscesses, predominantly
in skin folds that carry terminal hairs and apocrine glands. Healing
occurs with substantial scarring. The prevalence of acne inversa has
been estimated at 1 in 100 to 1 in 600. The female-to-male ratio in most
published series is between 2:1 and 5:1 (Jansen et al., 2001).

Jansen et al. (2001) provided a detailed history and review of the
disorder.

- Genetic Heterogeneity of Familial Acne Inversa

Familial acne inversa-2 (ACNINV2; 613736) is caused by
haploinsufficiency for the PSENEN gene (607632) on chromosome 19q13.1.
Familial acne inversa-3 (ACNINV3; 613737) is caused by
haploinsufficiency for the PSEN1 gene (104311) on chromosome 14q24.3,
making this disorder allelic to early-onset Alzheimer disease (607822).

CLINICAL FEATURES

Fitzsimmons et al. (1984) observed chronic hidradenitis suppurativa in a
total of 21 members (16 females, 5 males) from 3 English families. In 1
kindred, the condition was associated with acne conglobata (cystic acne)
and vertical transmission through 3 generations was documented. In the
other families, affected persons had a history of acne vulgaris with
comedone formation and 2 generations were affected. No male-to-male
transmission was documented; however, the authors stated that the
grandfather in their family B was probably affected and, if true, this
would mean one instance of father-to-son transmission. Several of the
females were obese, but none had diabetes.

Fitzsimmons et al. (1985) extended their studies to 23 families in which
they found a total of 62 affected persons.

Fitzsimmons and Guilbert (1985) reported a series based on 26 probands.
'Single gene transmission' was supported by the findings in 11 of these.
In another 3 families, a history of other affected persons was obtained;
in 9 families no history of other cases was found. Several of the
families included persons with acne conglobata alone or with
hidradenitis suppurativa.

INHERITANCE

Knaysi et al. (1968) found a positive family history in 3 of 18 patients
specifically questioned.

In order to test the validity of dominant inheritance in hidradenitis
suppurativa, Von der Werth et al. (2000) revisited 14 surviving probands
and their families initially reported by Fitzsimmons and Guilbert
(1985). Patients were evaluated by a newly devised, strict definition of
the disorder. Von der Werth et al. (2000) directly evaluated 132 family
members and detected 28 affected relatives, including 27 who were in the
group previously labeled as family history-positive. Nine cases had not
been detected previously, including 7 who developed symptoms after the
previous study had been completed. Eighteen cases were classified as
'possibly affected,' including 2 that were classified as 'definitely
affected' in the original study. All new cases in families with positive
histories for hidradenitis suppurativa were descended from affected
individuals, while none of the unaffected members of these families had
affected children. In all, they found that 27% of surviving first-degree
relatives were definitely affected, a figure lower than the 50% expected
in an autosomal dominant disease. However, if they included the
'possibly affected' individuals, the number of affected first-degree
relatives was 51%. They also detected a female-to-male predominance of
2:1.

MAPPING

Gao et al. (2006) performed a genomewide scan in a 4-generation Chinese
family with acne inversa and identified a locus at chromosome
1p21.1-1q25.3, with a maximum lod score of 3.26 at the marker D1S2624
(theta = 0.00). Haplotype analysis refined the locus to a 76-Mb region
flanked by D1S248 and D1S2711.

MOLECULAR GENETICS

Wang et al. (2010) identified 3 families segregating autosomal dominant
acne inversa who had heterozygous loss-of-function mutations in the
NCSTN gene. One family had a single-basepair deletion leading to a
frameshift (605254.0001). Another had exon skipping (605254.0002), and
the last family had a premature termination codon (605254.0003). Wang et
al. (2010) found mutations causing acne inversa in other components of
the gamma-secretase complex, PSENEN (607632) and PSEN1 (104311).

OTHER FEATURES

A relationship has been suggested between hidradenitis suppurativa and
the development of nonmelanoma skin cancer. To confirm this relationship
and to explore the risk of other cancers among patients with
hidradenitis suppurativa, Lapins et al. (2001) identified 2,119 patients
with hidradenitis suppurativa from a computerized database of hospital
discharge diagnoses from all hospitals in Sweden covering a period of 22
years. They searched the Swedish National Cancer Registry for
information on these patients and calculated standardized incidence
ratios to estimate relative risk. The risk of developing any cancer in
the cohort with hidradenitis suppurativa increased 50%. Statistically
significant risk elevations were observed for nonmelanoma skin cancer.
There was less convincing evidence that the risks of buccal and liver
cancer were also elevated in hidradenitis suppurativa patients.

PATHOGENESIS

Based on histopathologic studies of tissue from patients with acne
inversa and control specimens, Jansen et al. (2001) proposed a sequence
of events in the pathogenesis of acne inversa. The earliest inflammatory
event is a segmental rupture of the follicular epithelium, followed by
spilling of foreign body material, such as corneocytes, bacteria, sebum
products, and hairs, into the dermis. The dumping of foreign products
initiates an inflammatory response provoking foreign body granuloma, and
epithelial strands try to encapsulate the necrotic tissue. The apocrine
glands are not involved in the earliest stage of follicular
hyperkeratosis. Once rupture of the follicular epithelium has occurred,
the disease spreads rapidly. The draining sinus is a late complication,
leading to extensive, periodically inflamed lesions that are undermined
by a system of fistulas. Jansen et al. (2001) emphasized that apocrine
involvement is a secondary event in the disease process.

NOMENCLATURE

Jansen et al. (2001) stated that the term 'hidradenitis suppurativa' is
a misnomer for this condition because it is a defect of follicular
epithelium, not of the apocrine glands, as previously considered. They
suggested the term 'acne inversa.'

*FIELD* RF
1. Fitzsimmons, J. S.; Fitzsimmons, E. M.; Gilbert, G.: Familial
hidradenitis suppurativa: evidence in favour of single gene transmission. J.
Med. Genet. 21: 281-285, 1984.

2. Fitzsimmons, J. S.; Guilbert, P. R.: A family study of hidradenitis
suppurativa. J. Med. Genet. 22: 367-373, 1985.

3. Fitzsimmons, J. S.; Guilbert, P. R.; Fitzsimmons, E. M.: Evidence
of genetic factors in hidradenitis suppurativa. Brit. J. Derm. 113:
1-8, 1985.

4. Gao, M.; Wang, P.-G.; Cui, Y.; Yang, S.; Zhang, Y.-H.; Lin, D.;
Zhang, K.-Y.; Liang, Y.-H.; Sun, L.-D.; Yan, K.-L.; Xiao, F.-L.; Huang,
W.; Zhang, X.-J.: Inversa acne (hidradenitis suppurativa): a case
report and identification of the locus at chromosome 1p21.1-1q25.3. J.
Invest. Derm. 126: 1302-1306, 2006.

5. Jansen, T.; Altmeyer, P.; Plewig, G.: Acne inversa (alias hidradenitis
suppurativa). J. Europ. Acad. Derm. Venereol. 15: 532-540, 2001.

6. Knaysi, G. A.; Cosman, B.; Crikelair, G. F.: Hidradenitis suppurativa. JAMA 203:
19-22, 1968.

7. Lapins, J.; Ye, W.; Nyren, O.; Emtestam, L.: Incidence of cancer
among patients with hidradenitis suppurativa. Arch. Derm. 137: 730-734,
2001.

8. Von der Werth, J. M.; Williams, H. C.; Raeburn, J. A.: The clinical
genetics of hidradenitis suppurativa revisited. Brit. J. Derm. 142:
947-953, 2000.

9. Wang, B.; Yang, W.; Wen, W.; Sun, J.; Su, B.; Liu, B.; Ma, D.;
Lv, D.; Wen, Y.; Qu, T.; Chen, M.; Sun, M.; Shen, Y.; Zhang, X.:
Gamma-secretase gene mutations in familial acne inversa. Science 330:
1065 only, 2010.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Abscesses (in skin folds that carry terminal hairs and apocrine glands
including axillae, groin, anal fold, mons pubis, and scalp, but not
face);
Nodules;
Draining sinuses (late complication);
Fistula formation (late complication);
Scarring (late complication);
Dermal contractures (late complication);
HISTOLOGY:;
Segmental rupture of the follicular epithelium;
Foreign material, such as corneocytes, bacteria, sebum products, and
hair accumulated in the dermis;
Occluding spongiform infundibulofolliculitis;
Inflammation;
Foreign body granulomas;
Necrotic tissue encapsulated by epithelial strands;
Apocrine glands are secondarily involved

MISCELLANEOUS:
Chronic, relapsing condition

MOLECULAR BASIS:
Caused by mutation in the nicastrin gene (NCSTN, 605254.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 1/12/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
alopez: 02/08/2011
joanna: 9/12/2006
ckniffin: 1/12/2006

*FIELD* CN
Ada Hamosh - updated: 2/2/2011
Cassandra L. Kniffin - updated: 1/12/2006
Gary A. Bellus - updated: 2/3/2003
Gary A. Bellus - updated: 3/13/2001

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/12/2011
carol: 2/21/2011
alopez: 2/9/2011
alopez: 2/8/2011
terry: 2/2/2011
terry: 6/3/2009
wwang: 1/17/2006
ckniffin: 1/12/2006
alopez: 2/3/2003
alopez: 3/13/2001
mimadm: 9/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/4/1986

MIM 605254
*RECORD*
*FIELD* NO
605254
*FIELD* TI
*605254 NICASTRIN; NCSTN
;;ANTERIOR PHARYNX DEFECTIVE 2, C. ELEGANS, HOMOLOG OF; APH2
read more*FIELD* TX

DESCRIPTION

Nicastrin is a type-1 transmembrane glycoprotein that forms high
molecular mass gamma-secretase complexes with presenilin-1 (PS1; see
104311) and presenilin-2 (PS2; 600759) that are necessary for the
endoproteolysis of several type-1 transmembrane proteins, including
beta-amyloid precursor protein (beta-APP; 104760) and Notch receptor
(see 190198).

CLONING

Yu et al. (2000) used an anti-PS1 antibody to immunoextract PS1 and
tightly associated proteins from intracellular membrane fractions of
HEK293 cells expressing moderate levels of PS1. In addition to nicastrin
and the PS1 holoprotein, alpha- (116805) and beta-catenin (116806) were
also identified in the protein complex. Using the deduced amino acid
sequence of nicastrin, Yu et al. (2000) derived a full-length cDNA
(GenBank GENBANK AF240468) from partial cDNAs in public databases. The
nicastrin gene encodes an open reading frame of 709 amino acids
containing a putative N-terminal signal peptide, a long N-terminal
hydrophilic domain containing glycosylation, N-myristoylation, and
phosphorylation motifs, an approximately 20-residue hydrophobic putative
transmembrane domain, and a short hydrophilic C terminus of 20 residues.
Yu et al. (2000) could not identify any significant amino acid sequence
homology or strong motif similarity to other functionally characterized
proteins. The name nicastrin reflects the fact that the quest for the
molecular machinery causing the presenilin-associated forms of Alzheimer
disease (see 104300) began with a description of that disorder in
descendants of an extended family originating from the Italian village
of Nicastro (Feldman et al., 1963; Foncin et al., 1985).

GENE FUNCTION

Yu et al. (2000) observed that suppression of nicastrin expression in C.
elegans embryos induced a subset of notch/glp-1 phenotypes similar to
those induced by simultaneous null mutations in both presenilin homologs
of C. elegans. Nicastrin also bound C-terminal derivatives of beta-APP,
and modulated the production of the amyloid-beta peptide from these
derivatives.

Yu et al. (2000) generated missense mutations in a conserved hydrophilic
domain of nicastrin. Missense mutation of the conserved DYIGS motif to
AAIGS (residues 336 to 340) increased amyloid-beta-42 and
amyloid-beta-40 peptide secretion. Deletions in this domain inhibited
amyloid-beta production.

In a review article, Kopan and Goate (2002) discussed the evidence for
various proposed roles for nicastrin, including a role as regulator of
Notch signaling, a component of gamma-secretase, and a regulator of
presenilin localization and stabilization. The authors included a
summary of the identification of nicastrin and a brief discussion of
nicastrin as a genetic risk factor for Alzheimer disease.

Goutte et al. (2002) determined that the cell surface localization of
the Notch component Aph2, the C. elegans homolog of nicastrin, requires
Aph1 (see APH1A; 607629) and presenilins.

Using coimmunoprecipitation and nickel affinity pull-down approaches,
Lee et al. (2002) showed that nicastrin and presenilin heterodimers
physically associated with APH1A and APH1B (607630) in vivo.

Using coimmunoprecipitation experiments, Steiner et al. (2002) showed
that nicastrin interacts with PEN2 (607632). Upon RNA
interference-mediated downregulation of nicastrin, they observed a
reduction in PEN2 levels. Additionally, downregulation of PEN2 by RNA
interference was associated with impaired nicastrin maturation, reduced
presenilin levels, and deficient gamma-secretase complex formation.

Rozmahel et al. (2002) reported results from a mouse model indicating
that the cleavage of Notch at site S3 and of APP at the gamma-site are
distinct presenilin-dependent processes. The results also supported a
functional interaction between nicastrin and presenilins in vertebrates.

Using Western blot analysis and immunogold electron microscopy,
Pasternak et al. (2003) demonstrated that significant amounts of
nicastrin, Psen1, and App colocalized with Lamp1 (153330) in the outer
membranes of rat lysosomes. Furthermore, rat lysosomal membranes were
enriched in acidic gamma-secretase activity that was precipitable with
anti-nicastrin antibody.

Kaether et al. (2004) showed that the very C terminus of PS1 interacted
with the transmembrane domain of nicastrin.

MAPPING

By analysis of public genetic and transcriptional maps, Yu et al. (2000)
mapped the human nicastrin gene to a region of chromosome 1 near D1S1595
and D1S2844 that in 2 independent genomewide surveys (Kehoe et al.,
1999; Zubenko et al., 1998) generated evidence for genetic linkage
and/or allelic association with an Alzheimer disease susceptibility
locus.

MOLECULAR GENETICS

- Alzheimer Disease

Yu et al. (2000) did not identify any mutations or polymorphisms in the
open reading frame of nicastrin in affected members of 19 late-onset
familial Alzheimer disease pedigrees in which no obligate recombinants
were detected between Alzheimer disease and the 14-cM genetic interval
between D1S1595 and D1S2844 containing the nicastrin gene.

Nicastrin regulates gamma-secretase cleavage of the amyloid precursor
protein by forming complexes with presenilins, in which most mutations
causing familial early-onset Alzheimer disease (EOAD) have been found.
The nicastrin gene maps to 1q23, a region that shows evidence for
linkage to (Kehoe et al., 1999) and association with (Hiltunen et al.,
2001) late-onset Alzheimer disease (LOAD). Dermaut et al. (2002)
evaluated the contribution of genetic variations in NCSTN in 2 large
series of patients with EOAD (onset at or before age 65 years) and LOAD
(onset after age 65 years). In 78 familial EOAD cases, they found 14
NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent
mutations, and 1 missense mutation (N417Y). N417Y was thought not to be
pathogenic, since it did not alter amyloid-beta secretion in an in vitro
assay and its frequency was similar in case and control subjects.
However, SNP haplotype estimation in 2 population-based series of Dutch
patients with EOAD (116) and LOAD (240) indicated that the frequency of
1 SNP haplotype (designated HapB) was higher in the group with familial
EOAD (7%), compared with the LOAD group (3%) and control group (3%). In
patients with familial EOAD without the APOE epsilon-4 allele
(107741.0016), the HapB frequency further increased, to 14%, resulting
in a 4-fold increased risk (odds ratio = 4.1). These results were
considered compatible with an important role of gamma-secretase
dysfunction in the etiology of familial EOAD.

Orlacchio et al. (2002) found no association between 2 SNPs in the
coding region of the NCSTN gene and AD in an Italian population, even
when considering stratification for apoE, the presenilin genes, and APP.
Helisalmi et al. (2004) found no association between 4 SNPs in the NCSTN
gene, including 1 coding SNP and 3 noncoding SNPs, in a Finnish AD
population, even with stratification for apoE4 genotype. Although there
were borderline associations with some haplotypes defined by the SNPs,
the authors concluded that NCSTN has a minor role in AD as a genetic
risk factor in the Finnish population.

- Familial Acne Inversa

Wang et al. (2010) identified 3 families of Han Chinese origin
segregating autosomal dominant familial acne inversa (ACNINV1; 142690)
due to mutation in the NCSTN gene. All 3 of these mutations led to
haploinsufficiency. Wang et al. (2010) also identified mutation in the
gamma-secretase components PSENEN (607632) and PSEN1 (104311) causing
familial acne inversa.

*FIELD* AV
.0001
ACNE INVERSA, FAMILIAL, 1
NCSTN, 1-BP DEL, 1752G

In a 3-generation Han Chinese family segregating autosomal dominant
familial acne inversa (142690), Wang et al. (2010) identified a
single-basepair deletion at nucleotide 1752 of the NCSTN gene
(1752delG), leading to frameshift and a premature termination codon
(E584DfsX44). This mutation was not identified in chromosomes from 200
ethnically matched control individuals.

.0002
ACNE INVERSA, FAMILIAL, 1
NCSTN, IVS13, G-A, +1

In a 3-generation Han Chinese family segregating autosomal dominant
familial acne inversa (142690), Wang et al. (2010) identified a G-to-A
substitution at the +1 position of exon 13 of the NCSTN gene
(1551+1G-A). This mutation resulted in skipping of exon 13 and loss of
32 amino acids (A486_T517del) in the NCSTN gene, and in complete loss of
function or haploinsufficiency for this allele. This mutation was not
identified in chromosomes from 200 ethnically matched control
individuals.

.0003
ACNE INVERSA, FAMILIAL, 1
NCSTN, ARG117TER

In a 3-generation Han Chinese family segregating autosomal dominant
familial acne inversa (142690), Wang et al. (2010) identified
heterozygosity for a C-to-T transition at nucleotide 349 of the NCSTN
gene, resulting in an arg-to-stop substitution at codon 117 (R117X).
This mutation segregated with the phenotype and was not detected in 200
ethnically matched control individuals.

*FIELD* RF
1. Dermaut, B.; Theuns, J.; Sleegers, K.; Hasegawa, H.; Van den Broeck,
M.; Vennekens, K.; Corsmit, E.; St. George-Hyslop, P.; Cruts, M.;
van Duijn, C. M.; Van Broeckhoven, C.: The gene encoding nicastrin,
a major gamma-secretase component, modifies risk for familial early-onset
Alzheimer disease in a Dutch population-based sample. Am. J. Hum.
Genet. 70: 1568-1574, 2002.

2. Feldman, R. G.; Chandler, K. A.; Levy, L. L.; Glaser, G. H.: Familial
Alzheimer's disease. Neurology 13: 811-824, 1963.

3. Foncin, J.-F.; Salmon, D.; Supino-Viterbo, V.; Feldman, R. G.;
Macchi, G.; Mariotti, P.; Scoppetta, C.; Caruso, G.; Bruni, A. C.
: Demence presenile d'Alzheimer transmise dans une famille etendue. Rev.
Neurol. (Paris) 141: 194-202, 1985.

4. Goutte, C.; Tsunozaki, M.; Hale, V. A.; Priess, J. R.: APH-1 is
a multipass membrane protein essential for the Notch signaling pathway
in Caenorhabditis elegans embryos. Proc. Nat. Acad. Sci. 99: 775-779,
2002.

5. Helisalmi, S.; Dermaut, B.; Hiltunen, M.; Mannermaa, A.; Van den
Broeck, M.; Lehtovirta, M.; Koivisto, A. M.; Iivonen, S.; Cruts, M.;
Soininen, H.; Van Broeckhoven, C.: Possible association of nicastrin
polymorphisms and Alzheimer disease in the Finnish population. Neurology 63:
173-175, 2004.

6. Hiltunen, M.; Mannermaa, A.; Thompson, D.; Easton, D.; Pirskanen,
M.; Helisalmi, S.; Koivisto, A. M.; Lehtovirta, M.; Ryynanen, M.;
Soininen, H.: Genome-wide linkage disequilibrium mapping of late-onset
Alzheimer's disease in Finland. Neurology 57: 1663-1668, 2001.

7. Kaether, C.; Capell, A.; Edbauer, D.; Winkler, E.; Novak, B.; Steiner,
H.; Haass, C.: The presenilin C-terminus is required for ER-retention,
nicastrin-binding and gamma-secretase activity. EMBO J. 23: 4738-4748,
2004.

8. Kehoe, P.; Wavrant-De Vrieze, F.; Crook, R.; Wu, W. S.; Holmans,
P.; Fenton, I.; Spurlock, G.; Norton, N.; Williams, H.; Williams,
N.; Lovestone, S.; Perez-Tur, J.; Hutton, J.; and 10 others: A
full genome scan for late onset Alzheimer disease. Hum. Molec. Genet. 8:
237-245, 1999.

9. Kopan, R.; Goate, A.: Aph-2/nicastrin: an essential component
of gamma-secretase and regulator of Notch signaling and presenilin
localization. Neuron 33: 321-324, 2002.

10. Lee, S.-F.; Shah, S.; Li, H.; Yu, C.; Han, W.; Yu, G.: Mammalian
APH-1 interacts with presenilin and nicastrin and is required for
intramembrane proteolysis of amyloid-beta precursor protein and Notch. J.
Biol. Chem. 277: 45013-45019, 2002.

11. Orlacchio, A.; Kawarai, T.; Polidoro, M.; Stefani, A.; Orlacchio,
A.; St George-Hyslop, P. H.; Bernardi, G.: Association analysis between
Alzheimer's disease and the nicastrin gene polymorphisms. Neurosci.
Lett. 333: 115-118, 2002.

12. Pasternak, S. H.; Bagshaw, R. D.; Guiral, M.; Zhang, S.; Ackerley,
C. A.; Pak, B. J.; Callahan, J. W.; Mahuran, D. J.: Presenilin-1,
nicastrin, amyloid precursor protein, and gamma-secretase activity
are co-localized in the lysosomal membrane. J. Biol. Chem. 278:
26687-26694, 2003.

13. Rozmahel, R.; Mount, H. T. J.; Chen, F.; Nguyen, V.; Huang, J.;
Erdebil, S.; Liauw, J.; Yu, G.; Hasegawa, H.; Gu, Y.; Song, Y.-Q.;
Schmidt, S. D.; Nixon, R. A.; Mathews, P. M.; Bergeron, C.; Fraser,
P.; Westaway, D.; St George-Hyslop, P.: Alleles at the Nicastrin
locus modify presenilin 1-deficiency phenotype. Proc. Nat. Acad.
Sci. 99: 14452-14457, 2002.

14. Steiner, H.; Winkler, E.; Edbauer, D.; Prokop, S.; Basset, G.;
Yamasaki, A.; Kostka, M.; Haass, C.: PEN-2 is an integral component
of the gamma-secretase complex required for coordinated expression
of presenilin and nicastrin. J. Biol. Chem. 277: 39062-39065, 2002.

15. Wang, B.; Yang, W.; Wen, W.; Sun, J.; Su, B.; Liu, B.; Ma, D.;
Lv, D.; Wen, Y.; Qu, T.; Chen, M.; Sun, M.; Shen, Y.; Zhang, X.:
Gamma-secretase gene mutations in familial acne inversa. Science 330:
1065 only, 2010.

16. Yu, G.; Nishimura, M.; Arawaka, S.; Levitan, D.; Zhang, L.; Tandon,
A.; Song, Y.-Q.; Rogaeva, E.; Chen, F.; Kawarai, T.; Supala, A.; Levesque,
L.; and 18 others: Nicastrin modulates presenilin-mediated notch/glp-1
signal transduction and beta-APP processing. Nature 407: 48-54,
2000.

17. Zubenko, G. S.; Hughes, H. B.; Stiffler, J. S.; Hurtt, M. R.;
Kaplan, B. B.: A genome survey for novel Alzheimer disease risk loci:
results at 10-cM resolution. Genomics 50: 121-128, 1998.

*FIELD* CN
Ada Hamosh - updated: 2/2/2011
Patricia A. Hartz - updated: 2/23/2006
Cassandra L. Kniffin - updated: 3/4/2005
Dawn Watkins-Chow - updated: 3/17/2003
Victor A. McKusick - updated: 12/13/2002
Dawn Watkins-Chow - updated: 7/30/2002
Victor A. McKusick - updated: 6/12/2002

*FIELD* CD
Ada Hamosh: 9/6/2000

*FIELD* ED
terry: 06/11/2012
carol: 12/12/2011
alopez: 2/8/2011
terry: 2/2/2011
mgross: 3/31/2006
terry: 2/23/2006
alopez: 4/13/2005
wwang: 3/15/2005
ckniffin: 3/4/2005
alopez: 9/9/2004
mgross: 3/17/2003
tkritzer: 12/18/2002
tkritzer: 12/17/2002
terry: 12/13/2002
tkritzer: 7/30/2002
alopez: 6/14/2002
terry: 6/12/2002
alopez: 9/7/2000
alopez: 9/6/2000

RBCC Red Blood Cell Collection

Full text data of NCSTN