Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex

A. Letai, P. A. Coulombe, M. B. McCormick, Q. C. Yu, E. Hutton, E. Fuchs

Research output: Contribution to journalArticlepeer-review


Keratins are the major structural proteins of the epidermis. Recently, it was discovered that point mutations in the epidermal keratins can lead to the blistering skin diseases epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH), involving epidermal cell fragility and rupture upon mechanical stress. In this study, we demonstrate a correlation between disease severity, location of point mutations within the keratin polypeptides, and degree to which these mutations perturb keratin filament structure. Interestingly, of the 11 EBS or EH mutations thus far identified, 6 affect a single highly evolutionarily conserved arginine residue, which, when mutated, markedly perturbs keratin filament structure and keratin network formation. This site also appears to be a hot spot for mutation by CpG methylation and deamination. In the four epidermal keratins, there are several other CpG dinucleotides that exist at codons within the highly conserved ends of the keratin rod. To elucidate why mutations at these sites have not been detected in severe cases of EBS, we engineered 7 of these C → T transitions in K14 and tested their ability to perturb keratin network formation and keratin filament assembly in vitro. The effects of these mutants on keratin filament network formation were significantly less severe than the EBS/EH arginine mutation, suggesting that the high incidence of mutations of the residue in EBS and EH patients is a result of both a special sensitivity of filament structure to perturbations in this residue and its susceptibility to mutagenesis.

Original languageEnglish (US)
Pages (from-to)3197-3201
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
StatePublished - 1993
Externally publishedYes


  • 10-nm filament structure
  • keratin disorder

ASJC Scopus subject areas

  • General


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