From single nucleotide substitutions up to chromosomal deletions: genetic pause of leucism-associated disorders in animals.

Leucism is characterized by a complete or partial white skin and hair in combination with pigmented irides, which can be vivid blue or heterochromatic. This is due to a complete or partial lack of melanocytes. The underlying pathogenesis is a disturbed emigration or differentiation of neural crest-derived cells. Therefore, leucistic phenotypes can be associated with defects, which mainly impair sensory organs and nerves. In humans, a well-known example is the Waardenburg syndrome. Leucism-associated disorders were also described in mouse, rat, hamster, rabbit, mink, cat, dog, pig, sheep, llama, alpaca, cattle and horse. In some of these species already identified causal mutations affect the genes EDN3, EDNRB, KIT, MITF, PAX3, SILV and SOX10. Defect alleles represent different types of genetic variation, ranging from single nucleotide substitutions up to larger chromosomal deletions. Some of the defect alleles produce desired coat color patterns. In some but not all cases, available genetic tests enable breeders to avoid production of animals affected by a leucism-associated disorder.

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 white lambs with light blue eyes were sired from the same ram and died within a few hours up to a few days after birth, some of them with signs of intestinal obstruction. The aim of this study was to investigate if the observed hypopigmentation and a possible lethal condition were associated with a molecular change at the ovine EDNRB locus, and to check if such a genetic alteration also occurs in other Cameroon sheep flocks. Sequence analysis revealed a deletion of about 110 kb on sheep chromosome 10, comprising the entire EDNRB gene, on both chromosomes in the two available hypopigmented lambs and on a single chromosome in the two dams and three other unaffected relatives. This micro-chromosomal deletion was also confirmed by quantitative real-time PCR and by fluorescence in situ hybridization. Genotyping of a total of 127 Cameroon sheep in 7 other flocks by duplex PCR did not identify additional carriers of the deletion. Although both hypopigmented lambs 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 number and distribution. This is to our knowledge the first description of an ENDRB gene deletion and associated clinical signs in a mammalian species different from humans and rodents. In humans and rats it is postulated that the variable presence and severity of intestinal aganglionosis and other features in individuals with EDNRB deletion is due to a variable genetic background and multiple gene interactions. Therefore the here analyzed sheep are a valuable animal model to test these hypotheses in another species.