Skin integrity is essential for protection from external stress and trauma. Defects in structural proteins such as keratins cause skin fragility, epitomized by epidermolysis bullosa (EB), a life-threatening disorder. Here we show that dominant mutations of KLHL24, encoding a cullin 3–RBX1 ubiquitin ligase substrate receptor, cause EB. We have identified start-codon mutations in the KLHL24 gene in five patients with EB. These mutations lead to truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than its wild-type counterpart owing to abolished autoubiquitination. We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, we have confirmed that the Klhl24 mutations lead to stabilized Klhl24-ΔN28 and cause Krt14 degradation. Our findings identify a new disease-causing mechanism due to dysregulation of autoubiquitination and open new avenues for the treatment of related disorders.
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NCBI Reference Sequence
Sequence Read Archive
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We thank J. Jin, G. Ou, L. Yu, G. Xu and N. Zheng for advice and support, A. Elia, M. Emanuele and S. Elledge for critical reading of the manuscript, and all the patients and their families for participating in this study. This work was supported by the National Natural Science Foundation of China (grants 81201220 to Z.L., 81271744 to Y.Y. and 31670777 to X.T.), the Young Thousand Talents Program of China to X.T., China National Funds for Distinguished Young Scientists (grant 81425020 to Y.Y.), China National Funds for Excellent Young Scientists (grant 81522037 to Z.L.) and the Beijing Nova Program (grant Z151100000315044 to Z.L.).
The authors declare no competing financial interests.
Supplementary Text and Figures
Supplementary Figures 1–17 and Supplementary Tables 1–3. (PDF 1846 kb)
Supplementary Table 4
Sequences of primers, sgRNAs, siRNAs and probes used in the study. (XLSX 39 kb)
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Lin, Z., Li, S., Feng, C. et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet 48, 1508–1516 (2016). https://doi.org/10.1038/ng.3701