Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

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Serval ID
serval:BIB_7624ECA7AC18
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.
Journal
Journal of Biological Chemistry
Author(s)
Schneider P., Street S.L., Gaide O., Hertig S., Tardivel A., Tschopp J., Runkel L., Alevizopoulos K., Ferguson B.M., Zonana J.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Publication state
Published
Issued date
2001
Volume
276
Number
22
Pages
18819-18827
Language
english
Abstract
Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.
Keywords
Alternative Splicing, Amino Acid Sequence, Cell Line, Chromatography, Gel, Dimerization, Dose-Response Relationship, Drug, Ectodermal Dysplasia/genetics, Ectodysplasins, Enzyme-Linked Immunosorbent Assay, Exons, Furin, Genetic Linkage, Glycosylation, Humans, Introns, Ligands, Membrane Proteins/chemistry, Membrane Proteins/genetics, Molecular Sequence Data, Mutation, Phenotype, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins/metabolism, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Structure-Activity Relationship, Subtilisins/metabolism, Tumor Necrosis Factor-alpha/chemistry, X Chromosome/genetics
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:18
Last modification date
20/08/2019 14:33
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