A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns.

A de novoEDA-variant in a litter of shorthaired standard Dachshunds with X-linked hypohidrotic ectodermal dysplasia

“…The most obvious signs for XLHED were the partial alopecia with a consistent pattern among all four male cases and the tooth anomalies. This alopecia pattern is identical to those of dogs with confirmed cases of XLHED (Casal et al 1997; Waluk et al 2016) and also consistent with many other cases where XLHED is suspected (Moura and Cirio 2004), namely a bald forehead, abdomen and dorsal pelvic area. Secondly, the observed tooth anomalies are typical findings in XLHED (Lewis et al 2010).…”

“…Cases in other species include mice (Srivastava et al 1997), cattle (Drögemüller et al 2001), horse (Ramzan et al 2001), fish (Kondo et al 2001) and dogs. ED phenotypes were shown for the dog breeds Bichon Frisé (Grieshaber et al 1986), Labrador Retriever (Kunkle 1984), Miniature Poodle (Selmanowitz et al 1970b), Whippet (Thomsett 1961), Cocker Spaniel (Kral and Schwartzman 1964), Basset Hound (Chastain and Swayne 1985), mixed breeds of miniature Pinscher and Pekingese (Moura and Cirio 2004), German Shepherd (Casal et al 1997) and mixed breed dogs (Waluk et al 2016). ED phenotypes have been suspected in the breeds Belgian Shepherd, Beagle, Rottweiler, Yorkshire Terrier, French Bulldog and Lhasa Apso (Miller et al 2013).…”

Ade Novo EDA-Variant in a Litter of Shorthaired Standard Dachshunds with X-Linked Hypohidrotic Ectodermal Dysplasia

“…The most obvious signs for XLHED were the partial congenital hypotrichosis with a consistent pattern among all four male cases and the tooth anomalies. This congenital hypotrichosis pattern is identical to those of dogs with confirmed cases of XLHED (Casal et al 1997; Waluk et al 2016) and also consistent with many other cases where XLHED is suspected (Moura and Cirio 2004), namely a bald forehead, abdomen and dorsal pelvic area. Second, the observed tooth anomalies are typical findings in XLHED (Lewis et al 2010).…”

“…More than 80 causal mutations are described in humans (Huang et al 2015). A survey of ED cases in domestic animals (Srivastava et al 1997; Drögemüller et al 2001; Kondo et al 2001; Ramzan et al 2001), mainly focused on dogs (Thomsett 1961; Kral and Schwartzman 1964; Selmanowitz et al 1970b; Kunkle 1984; Chastain and Swayne 1985; Grieshaber et al 1986; Moura and Cirio 2004; Casal et al 2005; Drögemüller et al 2008; Olivry et al 2012; Miller et al 2013; Waluk et al 2016), is given in Table S1.…”

Canine NAPEPLD-associated models of human myelin disorders

“…The RNA samples were transformed into Illumina TruSeq libraries and 2 × 150 bp sequencing reads were obtained on a HiSeq3000 instrument (Illumina). RNA-seq data analysis was done as described before 52 .…”