Mutations in γ-secretase subunit-encoding PSENEN gene alone may not be sufficient for the development of acne inversa

Pengjun Zhou; Jingjing Liu; Tianxing Xu; Yanni Guo; Yue Han; Yanyan He; Lihang Lin; Xuemin Xiao

doi:10.1016/j.jdermsci.2021.06.007

Mutations in γ-secretase subunit-encoding PSENEN gene alone may not be sufficient for the development of acne inversa

J Dermatol Sci. 2021 Aug;103(2):73-81. doi: 10.1016/j.jdermsci.2021.06.007. Epub 2021 Jun 18.

Authors

Pengjun Zhou¹, Jingjing Liu², Tianxing Xu³, Yanni Guo³, Yue Han², Yanyan He⁴, Lihang Lin⁵, Xuemin Xiao⁶

Affiliations

¹ Department of Dermatology, The Union Hospital, Fujian Medical University, Fujian, China; Department of Dermatology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
² Department of Dermatology, The Union Hospital, Fujian Medical University, Fujian, China.
³ Department of Dermatology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
⁴ Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu, China.
⁵ Department of Dermatology, The Union Hospital, Fujian Medical University, Fujian, China. Electronic address: 460879404@qq.com.
⁶ Department of Dermatology, The Union Hospital, Fujian Medical University, Fujian, China. Electronic address: 258260101@qq.com.

PMID: 34330582
DOI: 10.1016/j.jdermsci.2021.06.007

Abstract

Background: The effects of PSENEN mutations in patients with acne inversa (AI) are poorly understood. Hyperproliferation of follicular keratinocytes and resulting occlusion may constitute the initial pathophysiology.

Objective: To investigate the effects of PSENEN knockdown on γ-secretase subunits, biological behaviors, and related signaling pathways in keratinocytes.

Methods: HaCaT cells were divided into an experimental group (PSENEN knock down), a negative control group, and a blank control group. Whole transcriptome sequencing was used to measure differences in mRNA expression of the whole genome; real-time PCR and Western blotting were performed to determine the interference efficiency and the effects of interference on the components of γ-secretase and related molecules. CCK-8 was used to measure cell proliferation, and flow cytometry was used to measure apoptosis and the cell cycle.

Results: A comparison of five healthy controls with three patients with PSENEN mutation (c.66delG, c.279delC, c.229_230insCACC) revealed decreased expression of mRNA and protein in skin lesions of the experimental group. In this group, expression of the other components of γ-secretase presenilin C-terminal fragment decreased, expression of immature nicastrin increased, expression of mature nicastrin decreased, and expression of anterior pharynx defective-1 remained unchanged. KEGG analysis revealed that differentially expressed molecules were enriched in m-TOR signaling pathways. Subsequent verification confirmed that differences in PI3K-AKT-mTOR signaling pathway molecules, cell proliferation, apoptosis, cell cycle and the expression levels of Ki-67, KRT1, and IVL between the groups were not statistically significant.

Conclusions: PSENEN mutations alone may be insufficient to cause the development of AI, or they may only induce a mild phenotype of AI.

Keywords: Acne inversa; EGFR signaling pathway; Hidradenitis suppurativa; PSENEN mutation; γ-Secretase.

MeSH terms

Amyloid Precursor Protein Secretases / genetics*
Amyloid Precursor Protein Secretases / metabolism
Case-Control Studies
Cell Line
Exome Sequencing
Gene Knockdown Techniques
Hidradenitis Suppurativa / genetics*
Hidradenitis Suppurativa / metabolism
Humans
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mutation
Signal Transduction

Substances

Membrane Proteins
PSENEN protein, human
Amyloid Precursor Protein Secretases