Stabilizing Mutations of KLHL24 Ubiquitin Ligase Cause Loss of Keratin 14 and Human Skin Fragility

The document reports on a study that found stabilizing mutations in the KLHL24 gene, which encodes a ubiquitin ligase substrate receptor, cause a form of epidermolysis bullosa (EB), a life-threatening skin disorder. The study identified start-codon mutations in KLHL24 in five patients with EB, leading to a truncated protein (KLHL24-ΔN28) that is more stable than the wild-type due to reduced autoubiquitination. This mutated protein causes excessive ubiquitination and degradation of keratin 14 (KRT14), a key structural protein in the skin. A knock-in mouse model confirmed that these mutations lead to Krt14 degradation. The findings suggest a new disease mechanism and potential treatment avenues for EB and related disorders.