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
View: Text | PDF
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

×

Figure 1

ADAM17 variant leads to ADWH.

Options: View larger image (or click on image) Download as PowerPoint
ADAM17 variant leads to ADWH. (A) Representative clinical pictures of p...
(A) Representative clinical pictures of patients with ADWH. (B) Hematoxylin and eosin (HE) staining of scalp tissues from patients and the normal controls. Scale bars, 125 μm. (C) The scanning electron microscopy (SEM) analysis revealed that the patient’s hair shaft displayed a nonuniform and abnormal cross-sectional shape. Furthermore, there was a substantial peeling of hair cuticle, which normally functions as the hair shaft’s outermost protective layer. Scale bars, 50 μm. (D) Pedigree of the family for patients. Hollow boxes represented the healthy men, while solid boxes represented the affected men. Hollow circles represented the healthy women, while solid circles represented the affected women in the family tree. The proband was identified with a black arrow. (E) A genome-wide linkage analysis provided evidence of linkage to chromosome 2, with a maximum LOD score of 3.18. (F) Gene sequencing revealed the heterozygous ADAM17 p.Asp647Asn (c.1939G>A) variant in patients. The arrows indicate the variant. (G) ADAM17 was predominantly expressed in the hair cortex, inner root sheath (IRS), and outer root sheath (ORS) of human hair follicle. Scale bar, 500 μm. (H) Schematic overview of ADAM17 protein and its domains. The p.D647N mutation was localized in CANDIS domain (indicated by a red arrow). SP, signal peptide; PD, pro-domain; Catalytic, catalytic metalloprotease domain; DD, disintegrin domain; MPD, membrane proximal domain; CANDIS, conserved ADAM17 seventeen dynamic interaction sequence; TM, transmembrane domain; CD, cytoplasmic domain. (I) Aspartic residue at position 647 is located within the conserved ADAM17 dynamic interaction sequence (CANDIS) domain of ADAM17, which is highly conserved.