title: An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture.
abstract: We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses, the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semidominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of four BR1 and 60 nonbrindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBTPS2 transcripts in skin, and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect cosegregation with the brindle phenotype in the investigated family, and was absent from 457 control horses of diverse breeds. Altogether, our genetic data, and previous knowledge on MBTPS2 function in the skin, suggest that the identified MBTPS2 intronic variant leads to partial exon skipping, and causes the BR1 phenotype in horses.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, 4000 Belgium.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Murgiano
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland.
authors.forename: Dominik P
authors.identifier: 0000-0003-1352-6282
authors.initials: DP
authors.lastname: Waluk
authors.affiliation: Institute of Medical Genetics, Cardiff University, CF14 4XN, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Towers
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wiedemar
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Drögemüller
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Balmer
authors.affiliation: Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, 4000 Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Druet
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland.
authors.forename: Arnaud
authors.identifier: 0000-0001-6503-5552
authors.initials: A
authors.lastname: Galichet
authors.affiliation: Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California 95617-1102.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Penedo
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001 Switzerland Clinic for Dermatology, Inselspital, Bern University Hospital, 3010 Switzerland.
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Roosje
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Institute of Medical Genetics, Cardiff University, CF14 4XN, UK.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Welle
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland tosso.leeb@vetsuisse.unibe.ch.
authors.forename: Tosso
authors.identifier: 0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D005091:Exons / Q000235:genetics; D006197:Hair / Q000254:growth & development / Q000378:metabolism*; D006736:Horses / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics*; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics*; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology; D014960:X Chromosome / Q000235:genetics
chemical_list: D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human
keywords: Equus Caballus; X-chromosome; dermatology; hair; lines of Blaschko