Abstract
Members of the tumour-necrosis factor receptor (TNFR) family that contain an intracellular death domain initiate signalling by recruiting cytoplasmic death domain adapter proteins1,2. Edar is a death domain protein of the TNFR family that is required for the development of hair, teeth and other ectodermal derivatives3,4. Mutations in Edar—or its ligand, Eda—cause hypohidrotic ectodermal dysplasia in humans and mice3,4,5,6,7. This disorder is characterized by sparse hair, a lack of sweat glands and malformation of teeth8. Here we report the identification of a death domain adapter encoded by the mouse crinkled locus. The crinkled mutant has an hypohidrotic ectodermal dysplasia phenotype identical to that of the edar (downless) and eda (Tabby) mutants9. This adapter, which we have called Edaradd (for Edar-associated death domain), interacts with the death domain of Edar and links the receptor to downstream signalling pathways. We also identify a missense mutation in its human orthologue, EDARADD, that is present in a family affected with hypohidrotic ectodermal dysplasia. Our findings show that the death receptor/adapter signalling mechanism is conserved in developmental, as well as apoptotic, signalling.
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Acknowledgements
We thank the families and physicians who assisted in gathering clinical information and samples, in particular G. Lestringant. We also thank D. Moore and D. Dowhan for technical advice and reagents. This work was supported by grants from the NIH and the National Foundation for Ectodermal Dysplasias.
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Headon, D., Emmal, S., Ferguson, B. et al. Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 414, 913–916 (2001). https://doi.org/10.1038/414913a
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DOI: https://doi.org/10.1038/414913a
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