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- Title
Consequences of Two Different Amino-Acid Substitutions at the Same Codon in KRT14 Indicate Definitive Roles of Structural Distortion in Epidermolysis Bullosa Simplex Pathogenesis.
- Authors
Natsuga, Ken; Nishie, Wataru; Smith, Brian J; Shinkuma, Satoru; Smith, Thomasin A; Parry, David A D; Oiso, Naoki; Kawada, Akira; Yoneda, Kozo; Akiyama, Masashi; Shimizu, Hiroshi
- 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.
- Subjects
EPIDERMOLYSIS bullosa; AMINO acids; KERATIN; EPITHELIAL cells; MOLECULAR models
- Publication
Journal of Investigative Dermatology, 2011, Vol 131, Issue 9, p1869
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1038/jid.2011.143