A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

The swh/swh rat showed sparse hair, abnormal morphology of teeth, and absence of sweat glands. The ectoderm-derived glands, meibomian, preputial, and tongue glands, were absent. We mapped the swh mutation to the most telomeric part of rat Chr 7 and found a Pro153Ser missense mutation in the Edaradd gene. This mutation was located in the death domain of EDARADD, which is crucial for signal transduction and resulted in failure to activate NF-κB.These findings suggest that swh is a loss-of-function mutation in the rat Edaradd and indicate that the swh/swh rat would be an excellent animal model of HED that could be used to investigate the pathological basis of the disease and the development of new therapies.Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by sparse hair, oligodontia, reduced sweating, and defects in a number of other ectodermal organs [1]. A lack of sweat glands can lead to recurrent severe overheating. Thus, children with HED are at substantial risk of sudden death in infancy due to fatal hyperpyrexia [2].HED is caused by mutations in any of the three Eda pathway genes: ectodysplasin (Eda) [3,4], ED receptor (Edar) [5], and EDAR-associated death domain (Edaradd) [6]. They encode the ligand, receptor, and intracellular signal mediator of a single linear pathway, respectively. The Eda signaling pathway activates transcription factor NF-κB thereby playing an important role in embryonic development, especially in the development of ectodermally derived organs [1].In humans, there are three types of HED with different inheritance: X-linked HED, autosomal dominant HED, and autosomal recessive HED. X-linked HED is the most common form of HED and is caused by mutations in EDA. Autosomal HED is caused by mutations in EDAR or EDARADD. Currently, over 100 different mutations in the EDA gene are known, while only ~20 and 4 causative mutations have been found in EDAR and EDARADD, respectively [7].To date, four mouse models of HED are ava