Possibly relevant human trait(s) and/or gene(s) (MIM number): 277580

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Familiar Hypopigmentation Syndrome; Lethal White Syndrome

Mapping: Pauciullo et al. (2013) physically mapped the ovine EDNRB gene to chromosome OAR10q22, using "R-banding and propidium iodide-staining fluorescent in situ hybridization". This confirmed the initial mapping of the same gene by Iannuzzi et al. (2001).

Molecular basis: Using a comparative-candidate gene approach (based on similar clinical signs in humans, rats and horses), Lühken et al. (2012) reported "a deletion of about 110 kb on sheep chromosome [OVA]10, comprising the entire EDNRB gene" as being responsible for this disorder. Interestingly, they noted that this region corresponds to a fragile site in the ovine genome (see OMIA 000392-9940). Pauciullo et al. (2013) confirmed the result of Lühken et al. (2012), and showed that the EDNRB gene itself is approximately 21kb in length.

Clinical features: As reported by Lühken et al. (2012), "Two of the hypopigmented lambs were available for post-mortem examination. Instead of the common brown phenotype of Cameroon sheep . . . , one of the lambs was totally white, whereas the other was also white but had pigmented distal limb ends including the claws and black marks in a small perianal area . . . . In both lambs, the irides were coloured light blue . . . , instead of dark brown as it is usual for Cameroon sheep. Both showed a considerably dilated cecum . . . and remaining meconium. Histopathological examination of intestinal samples of both lambs revealed a normal number and distribution of ganglion cells which showed a homogenous faint labelling for synaptophysin by immunohistological investigation." To the extent that the "number and distribution of ganglion cells" are normal, this disorder is more akin to Waardenberg syndrome types 1 or 2. However, Pauciullo et al. (2013) state that this ovine disorder comprises a "hypopigmented phenotype and signs of intestinal obstruction similar to aganglionosis reminiscent of the LWFS [lethal white foal syndrome]". In other words, this ovine disorder is more akin to Waardenberg syndrome 4A, which comprises hypopigmentation and Hirschprung's disease (megacolon). Variability in the extent of colonic aganglionosis is also seen in rats affected with the homologous disorder (Lühken et al., 2012).

Breed: Cameroon.

Associated gene: