PSENEN (Presenilin Enhancer, Gamma-Secretase Subunit)
Essential component of the gamma-secretase complex involved in Notch signaling and Alzheimer's disease pathogenesis
Gene Information Card
| Symbol | PSENEN |
|---|---|
| Full Name | Presenilin Enhancer, Gamma-Secretase Subunit |
| Gene Type | Protein coding |
| Chromosomal Location | 19q13.12 |
| NCBI Gene ID | 55851 ncbi.nlm.nih.gov/gene/55851 |
| Ensembl ID | ENSG00000205155 |
| UniProt ID | Q9NZ42 |
| OMIM ID | 607632 |
| HGNC ID | 30100 |
| Aliases | PEN2, MDS033, HSPC182, PRO2809 |
Description
PSENEN (Presenilin Enhancer, Gamma-Secretase Subunit) encodes the PEN-2 protein, an essential component of the gamma-secretase complex. This multiprotein complex catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and the amyloid precursor protein (APP). PEN-2 is required for the proteolytic stability and activity of the gamma-secretase complex. Mutations in PSENEN are associated with familial hidradenitis suppurativa (acne inversa) and may contribute to Alzheimer's disease pathogenesis through altered APP processing.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Familial hidradenitis suppurativa (acne inversa) | Loss-of-function mutations in PSENEN impair gamma-secretase activity, disrupting Notch signaling in skin epithelium, leading to follicular occlusion and chronic inflammation. | OMIM #613736; PMID: 22521418 |
| Alzheimer's disease (potential modifier) | Altered gamma-secretase activity due to PSENEN variants may shift APP cleavage toward amyloidogenic Aβ42 production, though direct causal mutations are rare. | ClinVar; PMID: 15314685 |
| Dowling-Degos disease type 4 | Heterozygous missense mutations in PSENEN cause a rare form of reticulate pigmentation disorder via impaired gamma-secretase function in melanocytes. | OMIM #615537; PMID: 26297559 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | 12.5 | Medium |
| Heart (left ventricle) | 8.3 | Low |
| Liver | 6.1 | Low |
| Kidney | 9.7 | Low |
| Lung | 10.2 | Medium |
| Skin | 11.8 | Medium |
| Testis | 15.4 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 (embryonic kidney) | 14.2 | High expression; commonly used for gamma-secretase studies |
| SH-SY5Y (neuroblastoma) | 11.5 | Medium; neuronal model for APP processing |
| HeLa (cervical carcinoma) | 9.8 | Low |
| HepG2 (hepatocellular carcinoma) | 7.3 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.66_67insG (p.Gly23fs) | Frameshift | Rare | Loss of function; associated with hidradenitis suppurativa |
| c.1A>G (p.Met1?) | Start loss | Rare | Loss of function; associated with hidradenitis suppurativa |
| c.167T>C (p.Leu56Pro) | Missense | Rare | Impaired gamma-secretase assembly; Dowling-Degos disease type 4 |
| c.254A>G (p.Asn85Ser) | Missense | Rare | Reduced gamma-secretase activity; reported in hidradenitis suppurativa |
Mutation functional classification
Loss of Function (LOF)
Frameshift and start-loss mutations (e.g., c.66_67insG, c.1A>G) abolish PEN-2 protein function, leading to reduced gamma-secretase activity and impaired Notch signaling, causing hidradenitis suppurativa.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in PSENEN.
Dominant Negative (DN)
Missense mutations (e.g., p.Leu56Pro) may exert dominant-negative effects by disrupting gamma-secretase complex assembly and reducing overall proteolytic activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• KEGG hsa05010: Alzheimer's disease
• KEGG hsa04330: Notch signaling pathway
• Reactome R-HSA-157118: Signaling by NOTCH
• Reactome R-HSA-977225: Amyloid fiber formation
• Reactome R-HSA-9013508: NOTCH3 intracellular domain regulates transcription
Protein Summary
PEN-2 (Presenilin Enhancer 2) is a 101-amino acid transmembrane protein that serves as a critical subunit of the gamma-secretase complex. It is required for the endoproteolytic processing of presenilin (PSEN1/PSEN2) into N- and C-terminal fragments, which is essential for gamma-secretase activity. PEN-2 stabilizes the complex and facilitates its trafficking from the endoplasmic reticulum to the plasma membrane. The protein contains two transmembrane domains with both termini facing the lumen. Loss of PEN-2 function disrupts Notch signaling, leading to skin disorders, while its role in APP cleavage links it to Alzheimer's disease pathology.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PSENEN Knockout HEK293 Cell Line | EDJ-KQ979 | Human | 55851 | Details Get a Quote |
| PSENEN Knockout A-549 Cell Line | EDJ-KQ20001 | Human | 55851 | Details Get a Quote |
| PSENEN Knockout HCT 116 Cell Line | EDJ-KQ20002 | Human | 55851 | Details Get a Quote |
| PSENEN Knockout HeLa Cell Line | EDJ-KQ20003 | Human | 55851 | Details Get a Quote |
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