| 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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MedLine Citation:
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PMID: 21593775 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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.Journal of Investigative Dermatology advance online publication, 19 May 2011; doi:10.1038/jid.2011.143. |
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Authors:
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Ken Natsuga; Wataru Nishie; Brian J Smith; Satoru Shinkuma; Thomasin A Smith; David A D Parry; Naoki Oiso; Akira Kawada; Kozo Yoneda; Masashi Akiyama; Hiroshi Shimizu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-19 |
Journal Detail:
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Title: The Journal of investigative dermatology Volume: - ISSN: 1523-1747 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0426720 Medline TA: J Invest Dermatol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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