Homozygous deletion in MOCOS gene is associated with nephrologic syndrome in Tyrolean Grey. TG0496

Sporadic cases of renal syndromes are reported in domestic animals. We noticed two affected Tyrolean Grey 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 Grey cattle resembled inherited renal tubular dysplasia in Japanese Black cattle associated with mutations in the claudin 16 gene. 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 non-synonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026 gene (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 MOCOS have 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 MOCOS allele was absent from cattle of other breeds and about 4% heterozygous carriers were detected among 1201 genotyped Tyrolean Grey cattle. The identified MOCOS loss 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 MOCOS mutations and enables selection against this pathogenic variant in Tyrolean Grey cattle.