APH1A aph-1 homolog A, gamma-secretase subunit [Homo sapiens (human)] - Gene

Summary

Official Symbol: APH1Aprovided by HGNC
Official Full Name: aph-1 homolog A, gamma-secretase subunitprovided by HGNC
Primary source: HGNC:HGNC:29509
See related: Ensembl:ENSG00000117362 MIM:607629; AllianceGenome:HGNC:29509
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: APH-1; APH-1A; CGI-78; 6530402N02Rik
Summary: This gene encodes a component of the gamma secretase complex that cleaves integral membrane proteins such as Notch receptors and beta-amyloid precursor protein. The gamma secretase complex contains this gene product, or the paralogous anterior pharynx defective 1 homolog B (APH1B), along with the presenilin, nicastrin, and presenilin enhancer-2 proteins. The precise function of this seven-transmembrane-domain protein is unknown though it is suspected of facilitating the association of nicastrin and presenilin in the gamma secretase complex as well as interacting with substrates of the gamma secretase complex prior to their proteolytic processing. Polymorphisms in a promoter region of this gene have been associated with an increased risk for developing sporadic Alzheimer's disease. Alternative splicing results in multiple protein-coding and non-protein-coding transcript variants. [provided by RefSeq, Aug 2011]
Expression: Ubiquitous expression in thyroid (RPKM 47.4), colon (RPKM 37.4) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 1q21.2

Exon count:: 6

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	1	NC_000001.11 (150265404..150269016, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	1	NC_060925.1 (149390321..149393933, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	1	NC_000001.10 (150237804..150241416, complement)

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 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?

Specific Mutations in Aph1 Cause gamma-Secretase Activation.
Title: Specific Mutations in Aph1 Cause γ-Secretase Activation.
Using purified PSEN1/Aph1A gamma-secretase and the APPC99-3XFLAG substrate, authors show that substrate shortening progressively destabilizes the consecutive enzyme-substrate complexes that characterize the sequential gamma-secretase processing of APP; present a unifying model for how PSEN or APP mutations enhance amyloidogenic Abeta production, suggests that environmental factors may increase Alzheimer's Disease risk.
Title: Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.
Data show that presenilin 1 (PS1)/anterior-pharynx-defective protein 1 (Aph1b), presenilin 2 (PS2)/Aph1aL, PS2/Aph1aS and PS2/anterior pharynx defective 1 homolog B (Aph1b) gamma-secretase produced amyloid beta peptide (Abeta) with a higher Abeta42+Abeta43-to-Abeta40 (Abeta42(43)/Abeta40) ratio than the other gamma-secretases.
Title: Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase.
Data show that presenilin 1 (PS1)-containing gamma-secretase complexes were targeted to the plasma membrane, whereas presenilin 2 (PS2)-containing ones were addressed to the trans-Golgi network, to recycling endosomes.
Title: Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments.
No statistically significant difference was detected either in APOE or APH-1a polymorphisms, not suggesting a strong susceptibility to the development of Alzheimer disease.
Title: The effects and interactions of APOE and APH-1A polymorphisms in Alzheimer disease.
analysis of how the conformation of presenilin, Pen-2, Aph-1, and nicastrin affect the function and mechanism of gamma-secretase
Title: Structural basis of human γ-secretase assembly.
A loss of PS/gamma-secretase function to cleave Abeta42(43) may initiate Alzheimer's disease.
Title: γ-secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Aβ43.
We demonstrate that extending the transmembrane domain of the amyloid precursor protein-derived C99 substrate in proximity to the cytosolic face strongly influences gamma-secretase cleavage specificity.
Title: Substrate determinants in the C99 juxtamembrane domains differentially affect γ-secretase cleavage specificity and modulator pharmacology.
The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease
Title: The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease.
Coexpression of wild-type or S-palmitoylation-deficient APH1aL and nicastrin leads to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice.
Title: Reduced Alzheimer's disease ß-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin.

Submit: New GeneRIF Correction See all GeneRIFs (32)

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

EBI GWAS Catalog

Description
Biological insights from 108 schizophrenia-associated genetic loci. EBI GWAS Catalog EBI GWAS CatalogPubMed

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

SGC31751 (e-PCR)
- UniSTS:5665

MARC_7139-7140:992008251:1 (e-PCR)
- UniSTS:231303

MARC_7139-7140:996687542:1 (e-PCR)
- UniSTS:231303

D13S1659 (e-PCR)
- UniSTS:81328

SHGC-32182 (e-PCR)
- UniSTS:7100

A004F41 (e-PCR)
- UniSTS:47312

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables endopeptidase activator activity	IGI Inferred from Genetic Interaction more info	PubMed
enables endopeptidase activator activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables enzyme binding	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein-macromolecule adaptor activity	IBA Inferred from Biological aspect of Ancestor more info
enables protein-macromolecule adaptor activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
involved_in Notch receptor processing	IBA Inferred from Biological aspect of Ancestor more info
involved_in Notch receptor processing	IDA Inferred from Direct Assay more info	PubMed
involved_in Notch receptor processing	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in Notch receptor processing	NAS Non-traceable Author Statement more info	PubMed
involved_in Notch receptor processing	TAS Traceable Author Statement more info	PubMed
involved_in Notch signaling pathway	IBA Inferred from Biological aspect of Ancestor more info
involved_in amyloid precursor protein catabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in amyloid precursor protein catabolic process	IGI Inferred from Genetic Interaction more info	PubMed
involved_in amyloid precursor protein catabolic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in amyloid precursor protein catabolic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in amyloid precursor protein catabolic process	TAS Traceable Author Statement more info	PubMed
involved_in amyloid precursor protein metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in amyloid-beta formation	IDA Inferred from Direct Assay more info	PubMed
involved_in amyloid-beta formation	IGI Inferred from Genetic Interaction more info	PubMed
involved_in amyloid-beta formation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane protein ectodomain proteolysis	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane protein intracellular domain proteolysis	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane protein intracellular domain proteolysis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane protein intracellular domain proteolysis	ISS Inferred from Sequence or Structural Similarity more info
involved_in metanephros development	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of endopeptidase activity	IGI Inferred from Genetic Interaction more info	PubMed
involved_in positive regulation of endopeptidase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in protein processing	IBA Inferred from Biological aspect of Ancestor more info
involved_in protein processing	IDA Inferred from Direct Assay more info	PubMed
involved_in protein processing	IGI Inferred from Genetic Interaction more info	PubMed
involved_in protein processing	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
located_in Golgi cisterna membrane	IEA Inferred from Electronic Annotation more info
located_in Golgi membrane	NAS Non-traceable Author Statement more info	PubMed
located_in early endosome	IEA Inferred from Electronic Annotation more info
is_active_in endoplasmic reticulum	IBA Inferred from Biological aspect of Ancestor more info
located_in endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
located_in endoplasmic reticulum membrane	NAS Non-traceable Author Statement more info	PubMed
located_in endosome membrane	TAS Traceable Author Statement more info
part_of gamma-secretase complex	IBA Inferred from Biological aspect of Ancestor more info
part_of gamma-secretase complex	IDA Inferred from Direct Assay more info	PubMed
part_of gamma-secretase complex	IPI Inferred from Physical Interaction more info	PubMed
part_of gamma-secretase complex	ISS Inferred from Sequence or Structural Similarity more info
located_in membrane	HDA more info	PubMed
located_in membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in plasma membrane	TAS Traceable Author Statement more info
located_in presynaptic membrane	IEA Inferred from Electronic Annotation more info
located_in synaptic vesicle	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: gamma-secretase subunit APH-1A

Names: APH1A gamma secretase subunit; anterior pharynx defective 1 homolog A; aph-1alpha; presenilin-stabilization factor

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_029952.2 RefSeqGene

Range

5000..8612

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001077628.3 → NP_001071096.1 gamma-secretase subunit APH-1A isoform 1

See identical proteins and their annotated locations for NP_001071096.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1; also known as isoform L).

Source sequence(s)

BC020590, BI760743, DC365601

Consensus CDS

CCDS41390.1

UniProtKB/Swiss-Prot

B4DQK0, Q5TB22, Q5TB23, Q969R6, Q96BI3, Q9BVG0, Q9Y386

UniProtKB/TrEMBL

B3KQT0

Related

ENSP00000358105.3, ENST00000369109.8

Conserved Domains (1) summary

pfam06105
Location:3 → 233

Aph-1; Aph-1 protein
NM_001243771.2 → NP_001230700.1 gamma-secretase subunit APH-1A isoform 3

See identical proteins and their annotated locations for NP_001230700.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks a 5' exon and contains an alternate segement at the 3'end that results in a frameshift and premature stop codon, compared to variant 1. This variant encodes an isoform (3) with a shorter N-terminus and a shorter and distinct C-terminus, compared to isoform 1.

Source sequence(s)

AK300640, BC017699, BI760743, DC365601

UniProtKB/TrEMBL

B4DUG7

Conserved Domains (1) summary

pfam06105
Location:3 → 176

Aph-1; Aph-1 protein
NM_001243772.2 → NP_001230701.1 gamma-secretase subunit APH-1A isoform 4

See identical proteins and their annotated locations for NP_001230701.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks a 5' exon and lacks a segment of a 5' exon, compared to variant 1. This variant encodes an isoform (4) with a shorter and distinct N-terminus, compared to isoform 1.

Source sequence(s)

AK298832, BC017699, BI760743

Consensus CDS

CCDS58025.1

UniProtKB/Swiss-Prot

Q96BI3

Related

ENSP00000397473.2, ENST00000414276.6

Conserved Domains (1) summary

pfam06105
Location:3 → 163

Aph-1; Aph-1 protein
NM_016022.4 → NP_057106.2 gamma-secretase subunit APH-1A isoform 2

See identical proteins and their annotated locations for NP_057106.2

Status: REVIEWED

Description

Transcript Variant: This variant (2) contains an alternate segement in the 3' terminus that results in a frameshift and premature stop codon, compared to variant 1, and encodes an isoform (2; also known as isoform S) with a shorter and distinct C-terminus, compared to isoform 1.

Source sequence(s)

BC009501, BI760743, DC365601

Consensus CDS

CCDS41391.1

UniProtKB/TrEMBL

B3KQT0

Related

ENSP00000353380.4, ENST00000360244.8

Conserved Domains (1) summary

pfam06105
Location:3 → 233

Aph-1; Aph-1 protein

RNA

NR_045033.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (5) lacks an alternate segment of a 5' exon, compared to variant 1, which results in a frameshift and early stop codon. The transcript is sufficiently abundant to represent as a RefSeq record; however, the predicted protein is not represented because the product is significantly truncated and the transcript is a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK297680, BC008732, BI760743, DC365601
NR_045034.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (6) lacks multiple 5' exons, compared to variant 1, which results in a frameshift and early stop codon. The transcript is sufficiently abundant to represent as a RefSeq record; however, the predicted protein is not represented because the product is significantly truncated and the transcript is a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK307358, BC017699, BI760743
NR_045035.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (7) lacks a 5' exon, compared to variant 1, which results in a frameshift and early stop codon. The transcript is sufficiently abundant to represent as a RefSeq record; however, the predicted protein is not represented because the product is significantly truncated and the transcript is a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK298876, BC017699, BI760743, DC365601