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

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0426720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1747 (Electronic) Linking ISSN: 0022202X NLM ISO Abbreviation: J Invest Dermatol Subsets: MEDLINE
    • Publication Information:
      Publication: 2016- : New York : Elsevier
      Original Publication: Baltimore, Williams & Wilkins.
    • Subject Terms:
      Amino Acid Substitution/*genetics ; Codon/*genetics ; Epidermolysis Bullosa Simplex/*genetics ; Keratin-14/*chemistry ; Keratin-14/*genetics ; Keratinocytes/*physiology; Amino Acid Sequence ; Cell Line ; Child ; Cresols ; DNA Mutational Analysis ; Dimerization ; Drug Combinations ; Epidermolysis Bullosa Simplex/immunology ; Epidermolysis Bullosa Simplex/pathology ; Family Health ; Formaldehyde ; Humans ; Keratin-14/immunology ; Keratinocytes/cytology ; Male ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Protein Structure, Quaternary ; Resorcinols
    • Abstract:
      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.
    • Comments:
      Comment in: J Invest Dermatol. 2011 Sep;131(9):1787-90. (PMID: 21844930)
    • Accession Number:
      0 (Codon)
      0 (Cresols)
      0 (Drug Combinations)
      0 (KRT14 protein, human)
      0 (Keratin-14)
      0 (Resorcinols)
      1HG84L3525 (Formaldehyde)
      68812-80-6 (phenoaldehyde)
    • Publication Date:
      Date Created: 20110520 Date Completed: 20111014 Latest Revision: 20131121
    • Publication Date:
      20231215
    • Accession Number:
      10.1038/jid.2011.143
    • Accession Number:
      21593775