Human Gene NCSTN (uc001fvx.3) Description and Page Index
  Description: Homo sapiens nicastrin (NCSTN), mRNA.
RefSeq Summary (NM_015331): This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014].
Transcript (Including UTRs)
   Position: hg19 chr1:160,313,063-160,328,742 Size: 15,680 Total Exon Count: 17 Strand: +
Coding Region
   Position: hg19 chr1:160,313,187-160,328,061 Size: 14,875 Coding Exon Count: 17 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-14

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr1:160,313,063-160,328,742)mRNA (may differ from genome)Protein (709 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
neXtProtOMIMPubMedReactomeStanford SOURCETreefam

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Nicastrin; Flags: Precursor;
FUNCTION: Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta- amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex.
SUBUNIT: Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP).
INTERACTION: P49755:TMED10; NbExp=5; IntAct=EBI-998440, EBI-998422;
SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein (Potential). Melanosome. Note=Identified by mass spectrometry in melanosome fractions from stage I to stage IV.
TISSUE SPECIFICITY: Widely expressed.
INDUCTION: Constitutively expressed in neural cells.
DISEASE: Defects in NCSTN are the cause of familial acne inversa type 1 (ACNINV1) [MIM:142690]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.
SIMILARITY: Belongs to the nicastrin family.

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): NCSTN
CDC HuGE Published Literature: NCSTN
Positive Disease Associations: Alzheimer's Disease , Glucose
Related Studies:
  1. Alzheimer's Disease
    Helisalmi, S. et al. 2004, Possible association of nicastrin polymorphisms and Alzheimer disease in the Finnish population., Neurology. 2004 Jul;63(1):173-5. [PubMed 15249634]
    A significant difference in one haplotype was observed in AD patients without the APOE epsilon4 allele.
  2. Glucose
    , , . [PubMed 0]
  3. Glucose
    , , . [PubMed 0]
           more ... click here to view the complete list

-  MalaCards Disease Associations
  MalaCards Gene Search: NCSTN
Diseases sorted by gene-association score: acne inversa, familial, 1* (1230), acne (54), hidradenitis suppurativa (27), hidradenitis (26), alzheimer disease (12), sweat gland disease (12), anal canal squamous cell carcinoma (9), sebaceous gland disease (7), dowling-degos disease (4)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
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-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 42.88 RPKM in Cells - Transformed fibroblasts
Total median expression: 1129.18 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
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-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -45.30124-0.365 Picture PostScript Text
3' UTR -185.33681-0.272 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR008710 - Nicastrin

Pfam Domains:
PF04389 - Peptidase family M28
PF05450 - Nicastrin

SCOP Domains:
53187 - Zn-dependent exopeptidases

ModBase Predicted Comparative 3D Structure on Q92542
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserNo orthologGenome BrowserGenome BrowserNo ortholog
Gene DetailsGene Details Gene DetailsGene Details 
Gene SorterGene Sorter Gene SorterGene Sorter 
 RGD FlyBaseWormBase 
 Protein Sequence Protein SequenceProtein Sequence 
 Alignment AlignmentAlignment 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0004175 endopeptidase activity
GO:0005515 protein binding
GO:0008233 peptidase activity

Biological Process:
GO:0002262 myeloid cell homeostasis
GO:0006508 proteolysis
GO:0006509 membrane protein ectodomain proteolysis
GO:0007219 Notch signaling pathway
GO:0007220 Notch receptor processing
GO:0016485 protein processing
GO:0034205 beta-amyloid formation
GO:0035333 Notch receptor processing, ligand-dependent
GO:0042098 T cell proliferation
GO:0042982 amyloid precursor protein metabolic process
GO:0042987 amyloid precursor protein catabolic process
GO:0043085 positive regulation of catalytic activity
GO:0043312 neutrophil degranulation
GO:0050435 beta-amyloid metabolic process
GO:0050673 epithelial cell proliferation

Cellular Component:
GO:0005765 lysosomal membrane
GO:0005783 endoplasmic reticulum
GO:0005794 Golgi apparatus
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0005925 focal adhesion
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0030659 cytoplasmic vesicle membrane
GO:0031410 cytoplasmic vesicle
GO:0035577 azurophil granule membrane
GO:0042470 melanosome
GO:0070062 extracellular exosome
GO:0070765 gamma-secretase complex

-  Descriptions from all associated GenBank mRNAs
  AF240468 - Homo sapiens nicastrin mRNA, complete cds.
JD341643 - Sequence 322667 from Patent EP1572962.
BC047621 - Homo sapiens nicastrin, mRNA (cDNA clone MGC:51016 IMAGE:4827966), complete cds.
JD476192 - Sequence 457216 from Patent EP1572962.
AK314764 - Homo sapiens cDNA, FLJ95633, Homo sapiens nicastrin (NCSTN), mRNA.
AK310741 - Homo sapiens cDNA, FLJ17783.
AK299142 - Homo sapiens cDNA FLJ60331 complete cds, highly similar to Nicastrin precursor.
AY359120 - Homo sapiens clone DNA97004 ATAG1874 (UNQ1874) mRNA, complete cds.
AB383822 - Synthetic construct DNA, clone: pF1KSDA0253, Homo sapiens NCSTN gene for nicastrin precursor, complete cds, without stop codon, in Flexi system.
BC100024 - Homo sapiens cDNA clone IMAGE:30523794, containing frame-shift errors.
D87442 - Homo sapiens mRNA for KIAA0253 gene, partial cds.
CU690444 - Synthetic construct Homo sapiens gateway clone IMAGE:100020951 5' read NCSTN mRNA.
JF432369 - Synthetic construct Homo sapiens clone IMAGE:100073565 nicastrin (NCSTN) gene, encodes complete protein.
KJ902339 - Synthetic construct Homo sapiens clone ccsbBroadEn_11733 NCSTN gene, encodes complete protein.
AK296153 - Homo sapiens cDNA FLJ51641 complete cds, highly similar to Nicastrin precursor.
JD492329 - Sequence 473353 from Patent EP1572962.
JD367918 - Sequence 348942 from Patent EP1572962.
JD304329 - Sequence 285353 from Patent EP1572962.
JD313078 - Sequence 294102 from Patent EP1572962.
JD129741 - Sequence 110765 from Patent EP1572962.
JD122491 - Sequence 103515 from Patent EP1572962.
JD402274 - Sequence 383298 from Patent EP1572962.
JD145043 - Sequence 126067 from Patent EP1572962.
JD324638 - Sequence 305662 from Patent EP1572962.
JD049159 - Sequence 30183 from Patent EP1572962.
JD049160 - Sequence 30184 from Patent EP1572962.
JD146556 - Sequence 127580 from Patent EP1572962.
JD514792 - Sequence 495816 from Patent EP1572962.
JD300128 - Sequence 281152 from Patent EP1572962.
JD418880 - Sequence 399904 from Patent EP1572962.
JD123301 - Sequence 104325 from Patent EP1572962.
JD199319 - Sequence 180343 from Patent EP1572962.
JD161888 - Sequence 142912 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04330 - Notch signaling pathway
hsa05010 - Alzheimer's disease

Reactome (by CSHL, EBI, and GO)

Protein Q92542 (Reactome details) participates in the following event(s):

R-HSA-6798739 Exocytosis of azurophil granule membrane proteins
R-HSA-157353 NEXT1 is cleaved to produce NICD1
R-HSA-157640 NEXT2 is cleaved to produce NICD2
R-HSA-157648 NEXT4 is cleaved to produce NICD4
R-NUL-2197556 Gamma-secretase complex cleaves mNEXT2
R-HSA-2220988 NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
R-HSA-9013361 NEXT3 is cleaved to produce NICD3
R-HSA-193682 gamma-secretase cleaves the p75NTR transmembrane domain
R-HSA-1251997 Cleavage of ERBB4m80 by gamma-scretase complex
R-HSA-205112 gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
R-HSA-2534206 E-cadherin degradation by PS1:NCSTN (Gamma-secretase)
R-HSA-6798695 Neutrophil degranulation
R-HSA-157212 A third proteolytic cleavage releases NICD
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-1980150 Signaling by NOTCH4
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-1474228 Degradation of the extracellular matrix
R-HSA-168249 Innate Immune System
R-HSA-1980143 Signaling by NOTCH1
R-HSA-1980145 Signaling by NOTCH2
R-HSA-157118 Signaling by NOTCH
R-HSA-2644602 Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2894858 Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-9012852 Signaling by NOTCH3
R-HSA-193704 p75 NTR receptor-mediated signalling
R-HSA-1236394 Signaling by ERBB4
R-HSA-2682334 EPH-Ephrin signaling
R-HSA-204998 Cell death signalling via NRAGE, NRIF and NADE
R-HSA-1474244 Extracellular matrix organization
R-HSA-168256 Immune System
R-HSA-162582 Signal Transduction
R-HSA-2644603 Signaling by NOTCH1 in Cancer
R-HSA-73887 Death Receptor Signalling
R-HSA-9006934 Signaling by Receptor Tyrosine Kinases
R-HSA-422475 Axon guidance
R-HSA-5663202 Diseases of signal transduction
R-HSA-1266738 Developmental Biology
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: KIAA0253, NICA_HUMAN, NM_015331, NP_056146, Q5T207, Q5T208, Q86VV5, Q92542, UNQ1874/PRO4317
UCSC ID: uc001fvx.3
RefSeq Accession: NM_015331
Protein: Q92542 (aka NICA_HUMAN)
CCDS: CCDS1203.1

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_015331.2
exon count: 17CDS single in 3' UTR: no RNA size: 2944
ORF size: 2130CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 4460.00frame shift in genome: no % Coverage: 99.69
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
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-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.