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

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


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Case-Control Studies
  • Child, Preschool
  • Epidermolysis Bullosa / genetics*
  • Female
  • Genotype
  • Humans
  • Infant, Newborn
  • Keratin-14 / metabolism*
  • Male
  • Mice
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Proteolysis
  • Repressor Proteins / genetics*
  • Skin / metabolism
  • Ubiquitin / metabolism
  • Ubiquitination


  • Keratin-14
  • Repressor Proteins
  • Ubiquitin
  • kelch-like protein 24, human