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

• Published in: G3 : genes - genomes - genetics 2016-09, Vol.6 (9), p.2949-2954
• Main Authors: Waluk, Dominik P, Zur, Gila, Kaufmann, Ronnie, Welle, Monika M, Jagannathan, Vidhya, Drögemüller, Cord, Müller, Eliane J, Leeb, Tosso, Galichet, Arnaud
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Animals; Canis familiaris; Dogs; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Ectodermal Dysplasia - veterinary; Ectodysplasins - genetics; Exons - genetics; Genotype; Humans; Investigations; Male; Mutation; Phenotype; Polymorphism, Single Nucleotide; RNA Splicing - genetics; RNA-seq; skin; splicing; X Chromosome - genetics; X-chromosome
• ISSN: 2160-1836; 2160-1836
• DOI: 10.1534/g3.116.033225

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.