NCSTN Gene

The NCSTN gene (NCSTN stands for "nicastrin") is a protein-coding gene located on chromosome 1q23.2. Alternatively spliced transcript variants of this gene have been described, but the nature of some of these full-length variants has not yet been determined. A pseudogene of this gene is located on chromosome 21.

Nicastrin, encoded by the NCSTN gene, is a type I transmembrane glycoprotein, an integral component of the multimeric gamma-secretase complex. The gamma-secretase is a protein complex composed of four subunits. The respective subcomplexes perform different tasks. The enzyme cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for the assembly of the gamma-secretase complex. Cleavage of beta-amyloid precursor protein leads to amyloid beta-peptide, the major component of neuritic plaque and the characteristic plaque lesions in the brains of Alzheimer's disease patients.

NCSTN is a "hotspot gene" for hidradenitis suppurativa (Wu J et al. 2020). Together with NCSTN, the CAPNS1, ARNT, and PPARD genes are most highly co-expressed (Vossen ARJV et al. 2020). Mutations in the subunits of the enzyme gamma-secretase have been described in several family strains with familial hidradenitis suppurativa (HS). In a family of 23 members, an autosomal dominant inheritance pattern of HS was found with a splice site mutation (c.1912_1915delCAGT) in the NCSTN gene that resulted in a frameshift and subsequent premature arrest (Vossen ARJV et al. 2020). Wild-type NCSTN appears to be upregulated in myeloid cells such as monocytes and macrophages and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts.

1. Vossen ARJV et al (2020) A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance. J Eur Acad Dermatol Venereol 34:2353-2361.
2. Wu J et al (2020) Novel mutation of the NCSTN gene identified in a Chinese acne inversa family. Ann Dermatol 32:237-242.
3. Zhang Z et al. (2021) A novel mutation of the NCSTN gene in a Chinese hidradenitis suppurativa family with familial comedones as the main clinical manifestation. Int J Dermatol. doi: 10.1111/ijd.16021.