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PSENEN gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

PSENEN gene

The PSENEN gene provides instructions for creating a protein essential to the gamma-secretase complex, which regulates critical cell signaling pathways.

Normal Function

The PSENEN gene provides instructions for making a protein called gamma-secretase subunit PEN-2 (shortened to PEN-2). This protein is one part (subunit) of a complex called gamma- (γ-) secretase. PEN-2 processes another subunit of the complex, presenilin 1, which is produced from the PSEN1 gene. This step is necessary for the γ-secretase complex to be functional.

The γ-secretase complex is located in the membrane that surrounds cells, where it cuts apart (cleaves) many different proteins that span the cell membrane (transmembrane proteins). This cleavage is an important step in several chemical signaling pathways that transmit signals from outside the cell into the nucleus. One of these pathways, known as Notch signaling, is essential for the normal maturation and division of hair follicle cells and other types of skin cells. Notch signaling is also involved in normal immune system function.

Health Conditions Related to Genetic Changes

Hidradenitis suppurativa

Several variants (also known as mutations) in the PSENEN gene have been found to cause hidradenitis suppurativa, a chronic skin disease characterized by recurrent boil-like lumps (nodules) under the skin that develop in hair follicles. The nodules tend to become inflamed and painful, and they produce significant scarring as they heal.

PSENEN gene variants reduce the amount of functional PEN-2 produced in cells, so less of this protein is available to act as part of the γ-secretase complex. The resulting shortage of normal γ-secretase impairs cell signaling pathways, including Notch signaling. Although little is known about the mechanism, studies suggest that abnormal Notch signaling may promote the development of recurrent nodules in hair follicles and trigger inflammation in the skin.

Dowling-Degos disease

MedlinePlus Genetics provides information about Dowling-Degos disease.

Other Names for This Gene

  • gamma-secretase subunit PEN-2
  • hematopoietic stem/progenitor cells protein MDS033
  • MDS033
  • MSTP064
  • PEN-2
  • PEN2
  • PEN2_HUMAN
  • presenilin enhancer 2 homolog
  • presenilin enhancer gamma secretase subunit
  • presenilin enhancer gamma-secretase subunit

Frequently Asked Questions

Variants in the PSENEN gene reduce the production of functional PEN-2 protein, which is a critical component of the gamma-secretase complex. This shortage impairs the complex's ability to process transmembrane proteins, disrupting Notch signaling pathways. Since Notch signaling is vital for the normal maturation and division of hair follicle cells, its dysfunction leads to the chronic inflammation, nodules, and scarring characteristic of hidradenitis suppurativa. :: Can genetic testing for PSENEN variants be used to predict who will develop hidradenitis suppurativa?::While PSENEN variants are a known cause of hidradenitis suppurativa, genetic testing is not currently used as a standard predictive tool for the general population. The condition has a complex genetic architecture, and not all individuals with risk variants develop the disease. Testing is typically reserved for individuals with a strong family history or severe, early-onset cases to confirm a genetic etiology, rather than for screening asymptomatic individuals. :: Does identifying a PSENEN mutation change the treatment approach for hidradenitis suppurativa?::Currently, the identification of a PSENEN mutation does not alter the standard clinical management of hidradenitis suppurativa. Treatment remains focused on controlling inflammation and preventing scarring through measures such as topical or systemic antibiotics, biologics, and surgical intervention for severe nodules. However, knowing the genetic cause may help in genetic counseling for family members and could inform future research into targeted therapies that modulate Notch signaling. :: What other health conditions are associated with mutations in the PSENEN gene?::While hidradenitis suppurativa is the primary condition linked to PSENEN variants, the gamma-secretase complex is involved in multiple signaling pathways. Mutations in related genes, such as PSEN1, are associated with Alzheimer's disease and frontotemporal dementia. However, PSENEN-specific mutations are predominantly associated with hidradenitis suppurativa, and there is no established link to neurodegenerative disorders in the current clinical literature.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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