ADAM17 variant causes hair loss via ubiquitin ligase TRIM47–mediated degradation
Xiaoxiao Wang, … , Hui Zhang, Ming Li
Xiaoxiao Wang, … , Hui Zhang, Ming Li
Published May 21, 2024
Citation Information: JCI Insight. 2024;9(13):e177588. https://doi.org/10.1172/jci.insight.177588.
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Research Article Dermatology Genetics

ADAM17 variant causes hair loss via ubiquitin ligase TRIM47–mediated degradation

Abstract

Hypotrichosis is a genetic disorder characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in a disintegrin and a metalloproteinase domain 17 (ADAM17) gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knockin mice mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cell (HFSC) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase tripartite motif-containing protein 47 (TRIM47). ADAM17 variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected the Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of Notch intracellular domain rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.

Authors

Xiaoxiao Wang, Chaolan Pan, Luyao Zheng, Jianbo Wang, Quan Zou, Peiyi Sun, Kaili Zhou, Anqi Zhao, Qiaoyu Cao, Wei He, Yumeng Wang, Ruhong Cheng, Zhirong Yao, Si Zhang, Hui Zhang, Ming Li

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Figure 3

Adam17 (p.D647N) variant affects homeostasis of the HFSC niche in hair follicles.

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Adam17 (p.D647N) variant affects homeostasis of the HFSC niche in hair ...
(A) Phenotypes of wild-type (WT), Adam17D647N/+, and Adam17D647N/D647N mice after shaving back skin during telogen (P19) and monitoring initiation of the next hair cycle. Adam17 mutation impeded hair regeneration. (B) Statistical data on the proportion of the skin with pigmentation in mice after hair shaving. (n = 6 biological replicates.) (C) HE staining of back skin during second telogen (P63). Upper panel scale bars, 300 μm; lower panel scale bars, 50 μm. (D–F) WT hair follicles (HFs) possessed a 2-bulge architecture, whereas Adam17D647N/D647N HFs usually had only 1. (D) Statistical data on the proportion of 3 HF types. (n = 6 biological replicates.) (E) Immunofluorescence was performed on whole-mount back skin hair follicles at the second telogen stage using HFSC markers K15 and CD34. Scale bar, 100 μm. (F) Skin sections underwent immunofluorescence staining using antibodies specific to HFSC markers. Scale bars, 40 μm. (G) Fluorescence-activated cell sorting (FACS) analyses of HFSC populations sorted by high α6-integrin and CD34. Right upper panel: Quantification of CD34-positive/α6-high cells (indicated by the black square brackets) among epithelial cells in second telogen mice. (n = 4–6 biological replicates.) Right lower panel: Quantification of CD34-positive/Ki67-positive cells among epithelial cells in second telogen mice. (n = 4–6 biological replicates.) (H) HFSC differentiation was blocked in Adam17D647N/D647N mice. Scale bars, 40 μm. CD200, the marker of secondary hair germ. Bu, hair bulge. All experiments were repeated 3 times. Data were expressed as mean ± SD; *P < 0.05; **P < 0.01; ***P < 0.001; 1-way ANOVA (B and D); Mann-Whitney test (G: right upper panel); Kruskal-Wallis test (G: right lower panel).