Categories: Liver/biliary system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 605495 (gene) , 237450 (trait)

Links to MONDO diseases:

• MONDO:0009379: Rotor syndrome

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2018

Cross-species summary: in humans called 'Hyperbilirubinemia, Rotor type, digenic' or 'Rotor syndrome'

Species-specific name: Congenital photosensitivity and hyperbilirubinaemia

Species-specific description: A recessive disease characterized by congenital photosensitivity and hyperbilirubinaemia has been described in Southdown sheep in New Zealand (Cunningham et al., 1942) and the USA (Cornelius and Gronwall, 1968). Cornelius (1970) proposed that the disease is similar to Gilbert syndrome (listed in OMIA as OMIA:000496-9940 : Hyperbilirubinaemia I in Ovis aries), but identification of the causal variant by Posberg et al. (2018) identified that these sheep are a model for human Rotor syndrome. References relating to the disease have been moved from OMIA:000496-9940 to this entry [19/08/2023].

Inheritance: Breeding trials in New Zealand Southdown sheep revealed a recessive mode of inheritance (Hancock, 1950).

Molecular basis: Posberg et al. (2018) investigated "the genetic cause for congenital photosensitivity and hyperbilirubinemia (CPH) in Southdown sheep. ... Whole-genome sequencing was performed for a phenotypically normal Southdown sheep heterozygous for CPH. ... A nonsynonymous mutation at ovine Chr3:193,691,195, which generated a glycine-to-arginine amino acid change within the predicted Slco1b3 protein, was significantly associated with hyperbilirubinemia and predicted to be deleterious."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: The primary clinical sign is photosensitive facial dermatitis, due to the associated defect in liver uptake of phyllorerythrin. Signs first appear at around 6-8 weeks of age, when lambs begin to eat grass. If not protected from sunlight, affected lambs develop severe dermatitis, mostly around the face and ears, which becomes infected, and eventually sloughs. Death (usually with 2-3 weeks) is a result of starvation and exhaustion (Hancock, 1950). If the lambs are protected from sunlight, they eventually die within five years, from renal failure (Cuppage et al., 1979). The cause of this renal dysfunction is not known. [Researched by Philippa Beard]

Pathology: Post-mortem reveals green and yellow discolouration of tissues, testicular atrophy, renal fibrosis, and pulmonary oedema and ascites. No gross hepatic lesions are evident. The only remarkable histopathological finding is lipofuscin accumulation in hepatocytes (McGavin, 1972). The absence of gross structural liver abnormalities helps differentiate this disorder from other forms of secondary hepatic photosensitisation, such as facial eczema. [Researched by Philippa Beard]

Breed: South Down (Sheep) (VBO_0001611).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: