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We investigated a family of horses exhibiting vertically striped patterns in their hair coat texture. This phenotype is termed “brindle” by horse breeders. Pedigree analyses were suggestive of a monogenic X-chromosomal dominant mode of inheritance. The striped pattern in affected female horses followed the lines of Blaschko thought to be a consequence of female X chromosome inactivation with subsequent expansion of cell clones expressing either the wild-type or mutant allele. Thus the striped pattern in the brindle phenotype supports the putative X-chromosomal dominant mode of inheritance. We analyzed whole genome sequences of 4 brindle and 62 non-brindle horses. The analysis revealed a private variant in intron 11 of the MBPTS2gene encoding the membrane bound transcription factor peptidase, site 2. The variant was absent from 457 control horses of diverse breeds. Different missense mutations in the MBPTS2gene lead to three related genodermatoses in human patients: ichthyosis follicularis, atrichia and photophobia (IFAP, OMIM #308205), Olmsted syndrome (OMIM #300918), and keratosis follicularis spinulosa decalvans (OMIM #308800). As the equine variant was very close to an exon/intron boundary (c.1437+4T > C), we analyzed MBPTS2transcripts in skin RNA from an affected and a control horse. The control sample yielded only the expected RT-PCR band whereas in the affected animal we observed an additional aberrant transcript lacking the entire exon 10 and parts of exon 11. Our genetic data and the previous knowledge on MBTPS2 function suggest that the MBTPS2intronic variant leads to partial exon skipping and causes the brindle phenotype in horses.

Sporadic cases of renal syndromes are reported in domestic animals. We noticed two affected Tyrolean Gray identical twin calves showing inexorable weight loss, skeletal abnormalities and delayed development associated with kidney stones and other kidney abnormalities. The observed renal syndrome in Tyrolean Gray cattle resembled inherited renal tubular dysplasia in Japanese Black cattle associated with mutations in the claudin-16gene. Despite striking phenotypic similarities, no obvious presence of pathogenic variants in this candidate gene indicated locus heterogeneity. The family history of the cases suggested an autosomal recessive inheritance. We performed homozygosity mapping, sequenced the whole genome of one case, and detected two associated nonsynonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026gene (g.39038055C > G; c.926C > G), located in a 15 Mb sized region of homozygosity on BTA 8; and a homozygous 1 bp deletion in the molybdenum cofactor sulfurase(MOCOS) gene (g.21222030delC, c.1881delG, and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24. Pathogenic variants in MOCOShave been associated with inherited metabolic syndromes and xanthinuria in different species including Japanese Black cattle. The identified deletion is predicted to be highly disruptive, creating a frameshift and premature termination of translation resulting in severely truncated MOCOS proteins that lack two functionally essential domains. The variant MOCOSallele was absent from cattle of other breeds, and about 4% heterozygous carriers were detected among 1201 genotyped Tyrolean Gray cattle. The identified MOCOSloss of function variant highly likely causes the renal syndrome in the affected animals. We suggest that the phenotypic features of the renal syndrome were related to an extremely severe early onset form of xanthinuria, which highly likely led to the progressive defects. The identification of this candidate causative mutation thus widens the known phenotypic spectrum of MOCOSmutations and enables selection against this pathogenic variant in Tyrolean Gray cattle.