Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex

Fuying Chen; Lei Yao; Xue Zhang; Yan Gu; Hong Yu; Zhirong Yao; Jia Zhang; Ming Li

doi:10.3389/fgene.2021.736610

Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex

Front Genet. 2021 Nov 29:12:736610. doi: 10.3389/fgene.2021.736610. eCollection 2021.

Authors

Fuying Chen^{1

2}, Lei Yao^{3

4}, Xue Zhang^{1

2}, Yan Gu^{1

2}, Hong Yu¹, Zhirong Yao^{1

2}, Jia Zhang^{1

2}, Ming Li^{1

2}

Affiliations

¹ Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ Experiment Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
⁴ Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Abstract

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.

Keywords: KRT5; desmoglein 1; genodermatosis; keratin; recessive EBS.