Mutation identification in a canine model of X-linked ectodermal dysplasia

Abstract

X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. In a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown to be involved in the morphogenesis of hair follicles and tooth buds during fetal development. Some human XHED patients also have concurrent immunodeficiency, due to mutations in the NF-κB essential modulator protein (IKBKG; formerly NEMO), which is also encoded on the X chromosome. In a breeding colony of dogs with XHED, immune system defects had been suspected because of frequent pulmonary infections and unexpected deaths resulting from pneumonia. To determine if defects in EDA or IKBKG cause XHED in the dogs, linkage analysis and sequencing experiments were performed. A polymorphic marker near the canine EDA gene showed significant linkage to XHED. The canine EDA gene was sequenced and a nucleotide substitution (G to A) in the splice acceptor site of intron 8 was detected in affected dogs. In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptorbinding site of ectodysplasin.

EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families

“…Autosomal recessive HED was also found to result from a mutation in the EDARADD gene on chromosome 1q42.2-q43 [16]. Interestingly, HED caused by mutations in either EDA or EDAR has been detected in several other species, including cattle [17], dogs [18] and mice [9,19,20]. Here we report the identification of a non-sense mutation in the EDAR gene in two large Swedish families with autosomal dominant (AD) HED.…”

A novel mutation of the bovine EDA gene associated with anhidrotic ectodermal dysplasia in Holstein cattle

“…Anhidrotic ectodermal dysplasia (EDA), also called hypohidrotic ectodermal dysplasia (HED) is a genetic disease characterized by the absence or hypoplasia of hair, teeth, and eccrine sweat glands that has been reported in humans (OMIM305100), the tabby mouse mutants, cattle and dogs (Kere et al 1996; Srivastava et al 1997; Drögemüller et al 2001; Casal et al 2005). Although most cases of EDA display X‐linked recessive inheritance, autosomal dominant and autosomal recessive forms also exist in humans (Shimomura et al 2004; van der Hout et al 2008).…”

Molecular and Therapeutic Characterization of Anti-ectodysplasin A Receptor (EDAR) Agonist Monoclonal Antibodies

“…EDAR-deficient OVE1B mice were as described previously (5). EDA-deficient dogs (19) were cared for in accordance with the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals and in the International Guiding Principles for Biomedical Research Involving Animals.…”