NCSTN nicastrin [Homo sapiens (human)] - Gene

Summary

Official Symbol: NCSTNprovided by HGNC
Official Full Name: nicastrinprovided by HGNC
Primary source: HGNC:HGNC:17091
See related: Ensembl:ENSG00000162736 MIM:605254
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: ATAG1874
Summary: 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]
Expression: Ubiquitous expression in placenta (RPKM 38.1), duodenum (RPKM 30.4) and 25 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 1q23.2

Exon count:: 19

Annotation release	Status	Assembly	Chr	Location
109.20200228	current	GRCh38.p13 (GCF_000001405.39)	1	NC_000001.11 (160343328..160358949)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	1	NC_000001.10 (160313063..160328742)

Chromosome 1 - NC_000001.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

The impaired EGFR signaling and its effects on epidermal differentiation were also observed in familial AI patients and Ncstn(DeltaKC) mice. Thus, our study showed that miR-30a-3p/RAB31/EGFR signaling pathway may play a key role in the pathogenesis of familial AI with NCSTN mutations.
Title: Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa.
A heterozygous nonsense mutation (c.617C>A, p.S206X) was identified in NCSTN in the proband. This mutation in NCSTN also existed in the other AI patients but not in the two normal relatives and 50 control subjects.
Title: Mutations in the γ-secretase genes PSEN1, PSENEN, and NCSTN in a family with acne inversa.
Identification of a novel deletion mutation in exon 4 of NCSTN, which may underlie the molecular pathogenesis in this Acne inversa family.
Title: A novel NCSTN gene mutation in a Chinese family with acne inversa.
A physical interaction between nicastrin (hNCT) and the gamma-secretase substrate amyloid beta-protein precursor (APPC100) confirmed the functionality of hNCT as a substrate recognizer.
Title: High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100.
The results show no differences in the decreased levels of inflammatory factors between patients with and without NCSTN mutations. This result may indicate that NCSTN mutations have no direct effect on inflammatory cells in the process of cytokine production.
Title: NCSTN mutations in hidradenitis suppurativa/acne inversa do not influence cytokine production by peripheral blood mononuclear cells.
The authors identified two nonsynonymous mutations in NCSTN in a white population, one of which had previously been described in African American and Chinese patients with HS. In addition, several intronic polymorphisms within the NCSTN were identified that were present at a significantly higher frequency in the HS population.
Title: Genetic analysis of NCSTN for potential association with hidradenitis suppurativa in familial and nonfamilial patients.
The results lead the investigators to speculate that NCSTN may be one of the genes determining the clinical phenotype of follicular HS .
Title: Phenotype of 53 Chinese individuals with nicastrin gene mutations in association with familial hidradenitis suppurativa (acne inversa).
Loss of function of nicastrin impacts on cell proliferation and differentiation-associated signalling pathways in a keratinocyte cell line.
Title: Nicastrin mutations in familial acne inversa impact keratinocyte proliferation and differentiation through the Notch and phosphoinositide 3-kinase/AKT signalling pathways.
analysis of two novel mutations segregating with familial hidradenitis suppurativa (acne inversa) and acne conglobate in NCSTN
Title: Expanding the spectrum of γ-secretase gene mutation-associated phenotypes: two novel mutations segregating with familial hidradenitis suppurativa (acne inversa) and acne conglobata.
Case Report: large Chinese family harboring novel NCSTN mutation associated with acne inversa.
Title: Characterization of a Novel Mutation in the NCSTN Gene in a Large Chinese Family with Acne Inversa.

Submit: New GeneRIF Correction See all GeneRIFs (83)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Familial acne inversa 1 MedGen: C4551962 OMIM: 142690 GeneReviews: Not available	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH36199 (e-PCR)
- UniSTS:38410

RH11634 (e-PCR)
- UniSTS:22843

RH71333 (e-PCR)
- UniSTS:27969

Homology

Homologs of the NCSTN gene: The NCSTN gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, A.thaliana, rice, and frog.
Orthologs from Annotation Pipeline: 311 organisms have orthologs with human gene NCSTN
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
endopeptidase activity	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
Notch receptor processing	IBA Inferred from Biological aspect of Ancestor more info	PubMed
Notch receptor processing	TAS Traceable Author Statement more info	PubMed
Notch receptor processing, ligand-dependent	TAS Traceable Author Statement more info
T cell proliferation	IEA Inferred from Electronic Annotation more info
adult behavior	IEA Inferred from Electronic Annotation more info
amyloid precursor protein biosynthetic process	IEA Inferred from Electronic Annotation more info
amyloid precursor protein catabolic process	TAS Traceable Author Statement more info	PubMed
amyloid precursor protein metabolic process	IDA Inferred from Direct Assay more info	PubMed
amyloid-beta formation	IMP Inferred from Mutant Phenotype more info	PubMed
cellular protein metabolic process	TAS Traceable Author Statement more info
cellular response to calcium ion	IEA Inferred from Electronic Annotation more info
central nervous system myelination	IEA Inferred from Electronic Annotation more info
cerebellum development	IEA Inferred from Electronic Annotation more info
dopamine receptor signaling pathway	IEA Inferred from Electronic Annotation more info
ephrin receptor signaling pathway	TAS Traceable Author Statement more info
epithelial cell proliferation	IEA Inferred from Electronic Annotation more info
glutamate receptor signaling pathway	IEA Inferred from Electronic Annotation more info
learning or memory	IEA Inferred from Electronic Annotation more info
membrane protein ectodomain proteolysis	IDA Inferred from Direct Assay more info	PubMed
membrane protein intracellular domain proteolysis	TAS Traceable Author Statement more info
myeloid cell homeostasis	IEA Inferred from Electronic Annotation more info
neuron apoptotic process	IEA Inferred from Electronic Annotation more info
neutrophil degranulation	TAS Traceable Author Statement more info
positive regulation of amyloid precursor protein biosynthetic process	IEA Inferred from Electronic Annotation more info
positive regulation of apoptotic process	TAS Traceable Author Statement more info
positive regulation of catalytic activity	IDA Inferred from Direct Assay more info	PubMed
protein processing	IBA Inferred from Biological aspect of Ancestor more info	PubMed
protein processing	IDA Inferred from Direct Assay more info	PubMed
proteolysis	NAS Non-traceable Author Statement more info	PubMed
regulation of long-term synaptic potentiation	IEA Inferred from Electronic Annotation more info
short-term synaptic potentiation	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
azurophil granule membrane	TAS Traceable Author Statement more info
early endosome	IEA Inferred from Electronic Annotation more info
endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
endosome membrane	TAS Traceable Author Statement more info
extracellular exosome	HDA more info	PubMed
focal adhesion	HDA more info	PubMed
gamma-secretase complex	IDA Inferred from Direct Assay more info	PubMed
gamma-secretase complex	NAS Non-traceable Author Statement more info	PubMed
integral component of membrane	IDA Inferred from Direct Assay more info	PubMed
integral component of membrane	NAS Non-traceable Author Statement more info	PubMed
integral component of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
integral component of plasma membrane	IDA Inferred from Direct Assay more info	PubMed
integral component of presynaptic membrane	IEA Inferred from Electronic Annotation more info
lysosomal membrane	HDA more info	PubMed
melanosome	IEA Inferred from Electronic Annotation more info
membrane	HDA more info	PubMed
mitochondrion	IEA Inferred from Electronic Annotation more info
plasma membrane	TAS Traceable Author Statement more info
sarcolemma	IEA Inferred from Electronic Annotation more info
synaptic vesicle	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: nicastrin

Names: anterior pharynx-defective 2

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_027935.1 RefSeqGene

Range

5111..20677

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001290184.2 → NP_001277113.1 nicastrin isoform 2

See identical proteins and their annotated locations for NP_001277113.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) has a different 5' structure resulting in translation initiation at an alternate AUG compared to variant 1; the 5'-most AUG, as used in variant 1, is associated with a truncated ORF that would render the transcript a candidate for nonsense-mediated decay (NMD). Leaky scanning may allow translation initiation at the alternate AUG resulting in a shorter isoform (2) with a distinct N-terminus compared to isoform 1.

Source sequence(s)

AL445230, BC047621, CN429672

UniProtKB/Swiss-Prot

Q92542

Conserved Domains (1) summary

cd03881
Location:155 → 462

M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex
NM_001290186.2 → NP_001277115.1 nicastrin isoform 3 precursor

See identical proteins and their annotated locations for NP_001277115.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks three alternate in-frame exons in the coding region compared to variant 1. The encoded isoform (3) is shorter than isoform 1.

Source sequence(s)

AF240468, AK299142, AL445230, CN429672

UniProtKB/Swiss-Prot

Q92542

UniProtKB/TrEMBL

B4DR82

Conserved Domains (1) summary

cl14876
Location:195 → 361

Zinc_peptidase_like; Zinc peptidases M18, M20, M28, and M42
NM_001349729.2 → NP_001336658.1 nicastrin isoform 4 precursor

Status: REVIEWED

Description

Transcript Variant: This variant (5) lacks an alternate in-frame exon in the 3' coding region, compared to variant 1. It encodes isoform 5, which is shorter than isoform 1.

Source sequence(s)

AL445230, H15133

Conserved Domains (1) summary

cd03881
Location:175 → 482

M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex
NM_015331.3 → NP_056146.1 nicastrin isoform 1 precursor

See identical proteins and their annotated locations for NP_056146.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1).

Source sequence(s)

AF240468, BC047621, CN429672

Consensus CDS

CCDS1203.1

UniProtKB/Swiss-Prot

Q92542

Related

ENSP00000294785.5, ENST00000294785.10

Conserved Domains (1) summary

cd03881
Location:175 → 482

M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000001.11 Reference GRCh38.p13 Primary Assembly

Range

160343328..160358949

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_005245053.5 → XP_005245110.1 nicastrin isoform X1

Conserved Domains (1) summary

cd03881
Location:175 → 395

M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex