PSENEN – Dowling-Degos Disease

PSENEN encodes presenilin enhancer protein 2 (Pen2), a core subunit of the γ-secretase complex essential for Notch receptor cleavage. Heterozygous truncating mutations in PSENEN have been identified in patients with autosomal dominant Dowling-Degos disease (DDD), a reticulate pigmentary disorder characterized by flexural reticulate hyperpigmentation and follicular anomalies.

Genetic analyses in a cohort of six unrelated individuals revealed six distinct heterozygous truncating variants in PSENEN (e.g., c.35T>A (p.Leu12Ter), c.62-1G>C) in DDD patients lacking KRT5, POFUT1, and POGLUT1 mutations (PMID:28287404). An independent study of four Jewish Ashkenazi families demonstrated a shared founder variant, c.168T>G (p.Tyr56Ter), co-segregating with a combined DDD–hidradenitis suppurativa phenotype (PMID:28922471).

Segregation analysis of the c.168T>G variant confirmed autosomal dominant inheritance in four families with multiple affected individuals (PMID:28922471). No phenocopies were reported, and all carriers exhibited classic flexural reticulate pigmentation.

Functional assays support a loss-of-function mechanism: psenen knockdown in zebrafish larvae recapitulated human DDD pigmentation defects and disturbed melanocyte migration (PMID:28287404). In patient keratinocytes harboring c.168T>G, Notch reporter assays revealed significantly reduced Notch signaling, consistent with impaired γ-secretase activity (PMID:28922471).

Collectively, truncating PSENEN variants cause haploinsufficiency of Pen2, disrupting γ-secretase–mediated Notch pathway signaling in skin. There are no conflicting reports disputing this association.

PSENEN genetic testing is recommended for individuals presenting with DDD, especially when accompanied by follicular abnormalities or hidradenitis suppurativa, to enable accurate diagnosis, familial risk assessment, and potential therapeutic targeting of Notch signaling. Key take-home: Heterozygous truncating PSENEN mutations underlie autosomal dominant DDD through Notch loss-of-function.

References

• The Journal of Clinical Investigation • 2017 • Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa PMID:28287404
• The British Journal of Dermatology • 2018 • A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN. PMID:28922471

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