title: 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.
authors.affiliation: Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3001, Switzerland DermFocus, University of Bern, 3001, Switzerland.
authors.forename: Dominik P
authors.identifier: 0000-0003-1352-6282
authors.initials: DP
authors.lastname: Waluk
authors.affiliation: Veterinary Teaching Hospital, The Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel.
authors.forename: Gila
authors.initials: G
authors.lastname: Zur
authors.affiliation: Veterinary Teaching Hospital, The Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: DermFocus, University of Bern, 3001, Switzerland Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Welle
authors.affiliation: DermFocus, University of Bern, 3001, Switzerland Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: DermFocus, University of Bern, 3001, Switzerland Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3001, Switzerland DermFocus, University of Bern, 3001, Switzerland Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001, Switzerland Clinic for Dermatology, Inselspital, Bern University Hospital, University of Bern, 3001, Switzerland.
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.affiliation: DermFocus, University of Bern, 3001, Switzerland Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Switzerland tosso.leeb@vetsuisse.unibe.ch arnaud.galichet@dkf.unibe.ch.
authors.forename: Tosso
authors.identifier: 0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
authors.affiliation: Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3001, Switzerland DermFocus, University of Bern, 3001, Switzerland tosso.leeb@vetsuisse.unibe.ch arnaud.galichet@dkf.unibe.ch.
authors.forename: Arnaud
authors.identifier: 0000-0001-6503-5552
authors.initials: A
authors.lastname: Galichet
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D004285:Dogs; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D053331:Ectodysplasins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics
chemical_list: D053331:Ectodysplasins
keywords: Canis familiaris; RNA-seq; X-chromosome; skin; splicing