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Nat Genet. 2016 Dec;48(12):1508-1516. doi: 10.1038/ng.3701. Epub 2016 Oct 31.

Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.

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Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Beijing, China.
Department of Dermatology, Tel Aviv Sourasky Medical Centre, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Laboratory of Electron Microscopy, Peking University First Hospital, Beijing, China.
BGI-Shenzhen, Shenzhen, China.
National Institute of Biological Sciences, Beijing, China.
Laboratory Animal Facility, Peking University First Hospital, Beijing, China.
Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
MOE Key Laboratory of Bioinformatics, School of Life Sciences and Centre of Biomedical Analysis, Tsinghua University, Beijing, China.


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.

[Indexed for MEDLINE]

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