| First Author | Lin Z | Year | 2016 |
| Journal | Nat Genet | Volume | 48 |
| Issue | 12 | Pages | 1508-1516 |
| PubMed ID | 27798626 | Mgi Jnum | J:327299 |
| Mgi Id | MGI:6151867 | Doi | 10.1038/ng.3701 |
| Citation | Lin Z, et al. (2016) Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet 48(12):1508-1516 |
| abstractText | 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-DeltaN28). KLHL24-DeltaN28 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-DeltaN28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, we have confirmed that the Klhl24 mutations lead to stabilized Klhl24-DeltaN28 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. |
