Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis

J Invest Dermatol. 2011 Sep;131(9):1869-76. doi: 10.1038/jid.2011.143. Epub 2011 May 19.


Numerous inherited diseases develop due to missense mutations, leading to an amino-acid substitution. Whether an amino-acid change is pathogenic depends on the level of deleterious effects caused by the amino-acid alteration. We show an example of different structural and phenotypic consequences caused by two individual amino-acid changes at the same position. Epidermolysis bullosa simplex (EBS) is a genodermatosis resulting from KRT5 or KRT14 mutations. Mutation analysis of an EBS family revealed that affected individuals were heterozygous for a, to our knowledge, previously unreported mutation of c.1237G>C (p.Ala413Pro) in KRT14. Interestingly, 2 of 100 unrelated normal controls were heterozygous, and 1 of the 100 was homozygous for a different mutation in this position, c.1237G>A (p.Ala413Thr). In silico modeling of the protein demonstrated deleterious structural effects from proline substitution but not from threonine substitution. In vitro transfection studies revealed a significantly larger number of keratin-clumped cells in HaCaT cells transfected with mutant KRT14 complementary DNA (cDNA) harboring p.Ala413Pro than those transfected with wild-type KRT14 cDNA or mutant KRT14 cDNA harboring p.Ala413Thr. These results show that changes in two distinct amino acids at a locus are destined to elicit different phenotypes due to the degree of structural distortion resulting from the amino-acid alterations.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / genetics*
  • Cell Line
  • Child
  • Codon / genetics*
  • Cresols
  • DNA Mutational Analysis
  • Dimerization
  • Drug Combinations
  • Epidermolysis Bullosa Simplex / genetics*
  • Epidermolysis Bullosa Simplex / immunology
  • Epidermolysis Bullosa Simplex / pathology
  • Family Health
  • Formaldehyde
  • Humans
  • Keratin-14 / chemistry*
  • Keratin-14 / genetics*
  • Keratin-14 / immunology
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Protein Structure, Quaternary
  • Resorcinols


  • Codon
  • Cresols
  • Drug Combinations
  • KRT14 protein, human
  • Keratin-14
  • Resorcinols
  • Formaldehyde
  • phenoaldehyde