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

Abstract

BackgroundHypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by sparse hair, oligodontia, and inability to sweat. It is caused by mutations in any of three Eda pathway genes: ectodysplasin (Eda), Eda receptor (Edar), and Edar-associated death domain (Edaradd), which encode ligand, receptor, and intracellular adaptor molecule, respectively. The Eda signaling pathway activates NF-κB, which is central to ectodermal differentiation. Although the causative genes and the molecular pathway affecting HED have been identified, no curative treatment for HED has been established. Previously, we found a rat spontaneous mutation that caused defects in hair follicles and named it sparse-and-wavy (swh). Here, we have established the swh rat as the first rat model of HED and successfully identified the swh mutation.ResultsThe 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.ConclusionsThese 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.

Design and application of a target capture sequencing of exons and conserved non-coding sequences for the rat

“…WTC- swh /Kyo is a rat model of hypohidrotic ectodermal dysplasia (HED) [ 35 ]. HED is known to be caused by mutations in genes encoding proteins involved in the Eda pathway, which include ectodysplasin ( Eda ), the ED receptor ( Edar ), and EDAR-associated death domain ( Edaradd ) [ 36 ].…”

“…In the case of WTC- swh /Kyo, previous linkage analysis revealed that the causative mutation resides in the distal end of rat chromosome 17 [ 27 ]. More recently, the locus was identified within a 161-kb interval between the microsatellite marker D17Rat140 (chr17:92,342,663) and the telomere [ 35 ]. We identified a total of 151,981 SNVs and 28,870 INDELs.…”

“…4 ), which changes proline to serine at codon 153 of the EDARADD protein, was predicted to be a damaging mutation. Indeed, this mutation was previously identified as causative for the HED phenotype [ 35 ].

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Need for Animal Models of Meibomian Gland Dysfunction

“…There are some pros and cons for each of the models reported. Several animal models are suitable for evaluation of developmental abnormalities of meibomian glands, for example, a mutation in the EDARadd gene resulted in rats with abnormal meibomian, sweat, mammary, and other exocrine glands [6]. Such models may or may not reflect acquired disease that obstruct the meibomian glands.…”

Atopic dermatitis-like skin lesions with IgE hyperproduction and pruritus in KFRS4/Kyo rats

“…For histological analysis, major organs including the skin were harvested, fixed in buffered 10% formalin, embedded in paraffin and stained with hematoxylin-eosin (HE) [17]. For examination of mast cells, skin sections were stained with toluidine blue (TB).…”