Polled and Multisystemic Syndrome (PMS) is a novel developmental disorder 
occurring in the progeny of a single bull. Its clinical spectrum includes 
polledness (complete agenesis of horns), facial dysmorphism, growth delay, 
chronic diarrhea, premature ovarian failure, and variable neurological and 
cardiac anomalies. PMS is also characterized by a deviation of the sex-ratio, 
suggesting male lethality during pregnancy. Using Mendelian error mapping and 
whole-genome sequencing, we identified a 3.7 Mb deletion on the paternal bovine 
chromosome 2 encompassing ARHGAP15, GTDC1 and ZEB2 genes. We then produced 
control and affected 90-day old fetuses to characterize this syndrome by 
histological and expression analyses. Compared to wild type individuals, 
affected animals showed a decreased expression of the three deleted genes. Based 
on a comparison with human Mowat-Wilson syndrome, we suggest that deletion of 
ZEB2, is responsible for most of the effects of the mutation. Finally 
sperm-FISH, embryo genotyping and analysis of reproduction records confirmed 
somatic mosaicism in the founder bull and male-specific lethality during the 
first third of gestation. In conclusion, we identified a novel locus involved in 
bovid horn ontogenesis and suggest that epithelial-to-mesenchymal transition 
plays a critical role in horn bud differentiation. We also provide new insights 
into the pathogenicity of ZEB2 loss of heterozygosity in bovine and humans and 
describe the first case of male-specific lethality associated with an autosomal 
locus in a non-murine mammalian species. This result sets PMS as a unique model 
to study sex-specific gene expression/regulation.