A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance

Abstract

Background: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS).

Objective: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project.

Methods: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system.

Results: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD.

Conclusion: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity.

Figure 1

The pedigree is consistent with autosomal dominant inheritance. Five individuals were investigated: HS2A (proband), HS2C and HS3B were affected by a frameshift mutation (p.S638 fs), while HS1A and HS2B were unaffected.

Figure 2

Phenotype of the proband with (1) overview of the right axilla with sinuses and scar contraction displaying Hurley stage II (2) patient on left lateral recumbent with gluteal involvement displaying Hurley stage III, wound contractions after surgical excision, and HS plaques in the upper leg (3) nodules/cysts (pencil marked) and atrophic scarring of the face and nape region, (4) overview of the scrotal, inguinal area including HS plaque in the medial thigh, (5) detail of scarring and folliculitis on the back, (6) overview of the left axilla with superficial lesions displaying Hurley stage II.

Figure 3

Sequence alignment of NCSTN in human and other species. The amino acid sequence is given in the one‐letter code. The deleted serine (S; yellow) located in the C‐terminus results in a frameshift. The altered sequence of mutated NCSTN (red) causes a premature stop (*). Conserved residues situated in the C‐terminus are indicated in bold (S; N; F, Y and W). Identical amino acids in human and murine are presented in grey boxes. WT: wildtype.

Figure 4

The gamma‐secretase complex with wildtype nicastrin (purple), presinilin‐1 (green), PEN‐2 (blue) and APH‐1 (orange). Mutated NCSTN with the C‐terminal deletion affects the tail of the protein resulting in a loss of interaction with the luminal and cytoplasmic membrane. The left panel displays wildtype NCSTN. The right panel displays mutated NCSTN.

Figure 5

OmniViz heatmap showing the top 25 co‐expressed genes related to NCSTN. Gene expression levels: red, upregulated genes compared to the geometric mean; blue, down‐regulated genes compared to the geometric mean. The colour intensity correlates with the degree of change. Abbreviations for co‐expressed genes of interest: ARNT: aryl hydrocarbon receptor nuclear transporter. PPARD: Peroxisome proliferator‐activated receptor delta. CAPNS1: Calpain Small Subunit 1.