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

    April 2017 in “ Journal of Investigative Dermatology ”
    Cheng Feng, Zhongxiao Lin, S. Li, H. Wang, Yan Yang, Xiaodan Tan
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    Studysummary This study identified that dominant mutations in the KLHL24 gene cause epidermolysis bullosa through dysregulated autoubiquitination, leading to excessive degradation of keratin 14. Our plain-language summary of this paper — not a Tressless recommendation.
    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.
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