ADAM17 variant causes hair loss via ubiquitin ligase TRIM47–mediated degradation
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
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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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 2

Adam17 (p.D647N) variant causes abnormal hair follicle morphology and hair loss in mice.

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Adam17 (p.D647N) variant causes abnormal hair follicle morphology and h...
(A) Hair coats and vibrissa hairs of wild-type (WT), Adam17D647N/+, and Adam17D647N/D647N mice at postnatal day (P) 19, P35, and 6 months (M). (B) Pelage hairs were observed under an optical microscope. Left and middle panel: compared with wild-type hairs, all 4 hair types of Adam17D647N/D647N pelage hairs showed waviness. Scale bars, 2 mm. Right panel: Adam17D647N/D647N mice displayed a significantly reduced proportion of primary and secondary hairs and a significant increase in the proportion of zigzag hairs. (n = 4 biological replicates.) (C) The scanning electron microscopy (SEM) analysis unveiled a peeling of the hair cuticle in the hair of Adam17D647N/D647N mice. Scale bar, 10 μm. (D) HE staining revealed notable structural abnormalities of hair follicles (HFs) in Adam17D647N/D647N mice at P28. Upper panel scale bars, 250 μm; lower panel scale bars, 50 μm. (E) HE staining of longitudinal sections revealed obvious structural abnormalities of HFs in Adam17D647N/D647N mice during the first anagen (P7) and second anagen (P28). Scale bars, 250 μm. (F) Immunofluorescence staining revealed a substantial decrease in IRS markers within the HFs of Adam17D647N/D647N mice, suggesting significant morphological abnormalities of the IRS. Scale bar, 100 μm. (G) A schematic illustration of HF layers and markers expressed in HF. (H) Immunoblot analysis of HF layer-specific markers in dorsal skin. (I) Transmission electron microscopy (TEM) of HFs at approximately 500 μm depth. Left panel scale bar, 5 μm; right panel scale bar, 2 μm. ORS, outer root sheath; IRS, inner root sheath; Cl, companion layer; He, Henle’s layer; Hu, Huxley’s layer; Cu, cuticle; Co, cortex; Me, medulla. 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).