Familiar Hypopigmentation Syndrome in Sheep Associated with Homozygous Deletion of the Entire Endothelin Type-B Receptor Gene

In humans, rodents and horses, pigmentary anomalies in combination with other disorders, notably intestinal aganglionosis,are associated with variants of the endothelin type-B receptor gene (EDNRB). In an inbred Cameroon sheep flock, five whitelambs with light blue eyes were sired from the same ram and died within a few hours up to a few days after birth, some ofthem with signs of intestinal obstruction. The aim of this study was to investigate if the observed hypopigmentation anda possible lethal condition were associated with a molecular change at the ovine EDNRB locus, and to check if such a geneticalteration also occurs in other Cameroon sheep flocks. Sequence analysis revealed a deletion of about 110 kb on sheepchromosome 10, comprising the entire EDNRB gene, on both chromosomes in the two available hypopigmented lambs andon a single chromosome in the two dams and three other unaffected relatives. This micro-chromosomal deletion was alsoconfirmed by quantitative real-time PCR and by fluorescence in situ hybridization. Genotyping of a total of 127 Cameroonsheep in 7 other flocks by duplex PCR did not identify additional carriers of the deletion. Although both hypopigmentedlambs available for post-mortem examination had a considerably dilated cecum and remaining meconium,histopathological examination of intestinal samples showed morphologically normal ganglion cells in appropriate numberand distribution. This is to our knowledge the first description of an ENDRB gene deletion and associated clinical signs ina mammalian species different from humans and rodents. In humans and rats it is postulated that the variable presence andseverity of intestinal aganglionosis and other features in individuals with EDNRB deletion is due to a variable geneticbackground and multiple gene interactions. Therefore the here analyzed sheep are a valuable animal model to test thesehypotheses in another species.