title: A single point mutation within the ED1 gene disrupts correct splicing at two different splice sites and leads to anhidrotic ectodermal dysplasia in cattle.
abstract: The ectodysplasin 1 gene ( ED1) encodes a signaling molecule of the tumor necrosis factor family that is involved in fetal development of ectodermal appendages. Mutations in the ED1 gene are responsible for X-linked anhidrotic ectodermal dysplasia characterized by impaired development of hair, teeth, and eccrine sweat glands in human, mouse, and cattle. Two isoforms of ectodysplasin 1, termed ED1-A1 and ED1-A2, arise by alternative splicing and bind to different receptors. We identified a novel ED1 splice site mutation in a cattle family with X-linked anhidrotic ectodermal dysplasia. The point mutation is located within a 5' splice site (splice donor) at the beginning of intron 8 that is used exclusively in the alternatively spliced ED1-A1 transcript. Remarkably, cDNA sequencing demonstrated that both physiological transcripts, i.e., the ED1-A1 and the ED1-A2 splice variant, were affected by this point mutation. In an affected animal, the use of cryptic internal splice donor and acceptor sites within exon 8 lead to the production of a single transcript lacking 51 or 45 bp with respect to the normal ED1-A1 or ED1-A2 transcripts, respectively. The translated protein of the mutated transcript contained a large deletion in the functionally important C-terminal tumor necrosis factor-like domain thus causing the observed phenotype of anhidrotic ectodermal dysplasia. Our findings suggest the presence of a splice enhancer in the ED1 gene in the region of the mutation.
authors.affiliation: Institute of Animal Breeding and Genetics, School of Veterinary Medicine Hannover, Bünteweg 17p, 30559 Hannover, Germany.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Martin
authors.initials: M
authors.lastname: Peters
authors.forename: Joachim
authors.initials: J
authors.lastname: Pohlenz
authors.forename: Ottmar
authors.initials: O
authors.lastname: Distl
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics*; D017931:DNA Primers; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000662:veterinary*; D053331:Ectodysplasins; D005091:Exons; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; C506018:EDA protein, human; D053331:Ectodysplasins; C506019:Eda protein, mouse; D008565:Membrane Proteins