An intronic MBTPS2 variant results in a splicing defect in horses with brindle coat texture

We investigated a family of horses exhibiting vertically striped patterns in their hair coat texture. This phenotype is termed “brindle” by horse breeders. Brindle horses show a healthy skin with no apparent lesions and no sign of illness. Hairs are “raised”, with a slightly different texture, shorter and set against the grain of the “normal” ones, on a slight angle, in this “Textured Brindle” pattern on the body. Pedigree analyses were suggestive of a monogenic X-chromosomal semi-dominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of 4 brindle and 62 non-brindled horses identified 60 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 (c.1437+4T>C) in intron 10 of the MBPTS2 gene. Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBPTS2 transcripts in skin and identified an additional aberrant transcript lacking the entire exon 10 and parts of exon 11, which was exclusively present in a brindle horse. The MBPTS2:c1437+4T>C variant showed perfect co-segregation with the brindle phenotype in the investigated family and was absent from 457 control horses of diverse breeds. Our genetic data and the previous knowledge on MBTPS2 function suggest that the identified MBTPS2 intronic variant leads to partial exon skipping and causes the brindle phenotype in horses.