Alternative titles; symbols
HGNC Approved Gene Symbol: NCSTN
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:160,343,383-160,358,949 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.2 | Acne inversa, familial, 1 | 142690 | Autosomal dominant | 3 |
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).
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 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).
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.
Cryoelectron Microscopy
The gamma-secretase complex, comprising presenilin (PSEN1; 104311), PEN2, APH1AL, and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Lu et al. (2014) reported the 3-dimensional structure of an intact human gamma-secretase complex at 4.5-angstrom resolution, determined by cryoelectron microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the transmembrane horseshoe. The nicastrin extracellular domain is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA.
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.
Dermaut et al. (2002) stated that the NCSTN gene maps to chromosome 1q23.
Familial Acne Inversa 1
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 (605254.0001-605254.0003). All 3 of the 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.
In a Caucasian man with hidradenitis suppurativa (acne inversa), Pink et al. (2011) identified heterozygosity for a splice site mutation in the NCSTN gene (605254.0004).
In a 3-generation Japanese family with hidradenitis suppurativa (HS), Takeichi et al. (2020) identified heterozygosity for a missense mutation in the NCSTN gene (G33R; 605254.0005) that segregated with disease and was not found in public variant databases.
In a 3-generation Japanese family with HS, Nishimori et al. (2020) identified heterozygosity for a nonsense mutation in the NCSTN gene (R429X; 605254.0006) that segregated with disease and was not found in the gnomAD database.
Associations Pending Confirmation
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.
In a 3-generation Han Chinese family segregating autosomal dominant familial acne inversa (ACNINV1; 142690), Wang et al. (2010) identified a heterozygous single-basepair deletion at nucleotide 1752 of the NCSTN gene (1752delG), leading to frameshift and a premature termination codon (Glu584AspfsTer44). This mutation was not identified in chromosomes from 200 ethnically matched control individuals.
In a 3-generation Han Chinese family segregating autosomal dominant familial acne inversa (ACNINV1; 142690), Wang et al. (2010) identified heterozygosity for 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 (Ala486_Thr517del) 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.
In a 3-generation Han Chinese family segregating autosomal dominant familial acne inversa (ACNINV1; 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.
In a Caucasian man with acne inversa (ACNINV1; 142690), Pink et al. (2011) identified heterozygosity for a splice site mutation (c.1101+1G-A) in intron 9 of the NCSTN gene. The mutation was not found in the proband's unaffected mother or in 200 control chromosomes of European ancestry; DNA was unavailable from his affected brother, father, or paternal grandfather. No variant transcript was detected, and RT-PCR showed significantly lower levels of NCSTN in the patient than in controls, suggesting that the mutant allele is subject to nonsense-mediated decay.
In affected members of a 3-generation Japanese family with hidradenitis suppurativa (ACNINV1; 142690), Takeichi et al. (2020) identified heterozygosity for a c.97G-A transition in the NCSTN gene, resulting in a gly33-to-arg (G33R) substitution at a highly conserved residue. The mutation segregated with disease and was not found in the HGVD or gnomAD databases. Among 6 affected individuals in the family, 3 also had severe chronic renal failure and were on hemodialysis. Immunohistochemistry showed lower staining intensity of nicastrin in patient skin than control samples, and immunoreactivity of Notch1 (190198) and Notch2 (600275) were lower in patient skin lesions than control skin samples.
In a Japanese man with hidradenitis suppurativa (ACNINV1; 142690), who died at age 44 of squamous cell carcinoma, Nishimori et al. (2020) identified heterozygosity for a c.1285C-T transition (c.1285C-T, NM_015331.2) in exon 11 of the NCSTN gene, resulting in an arg429-to-ter (R429X) substitution in the extracellular domain. His affected brother, mother, and maternal grandmother were also heterozygous for the mutation, which was not found in the gnomAD database. The female patients were said to be more mildly affected.
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