Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 600803 (trait) , 171060 (gene)

Mendelian trait/disorder: unknown

Considered a defect: yes

Year key variant first reported: 2010

Species-specific symbol: GBM

Inheritance: Mealey et al. (2010) initially proposed a dominant mode of inheritance with incomplete penetrance in Shetland Sheepdogs, based on the incomplete association between a proposed likely causal variant and disease phenotype. The authors acknowledged that further research is required. In a follow up study by Cullen et al. (2014) a multifactorial mode of inheritance as well as non-inherited etiology are discussed.

Molecular basis: Mealey et al. (2010): "An insertion (G) mutation in exon 12 of canine ABCB4 (ABCB4 1583_1584G) was found to be significantly associated with hepatobiliary disease in Shetland Sheepdogs specifically (P < 0.0001) as well as other breeds (P < 0.0006) [Cairn Terrier, Cocker Spaniel, Pomeranian]. ABCB4 1583_1584G results in a frame shift generating four stop codons that prematurely terminate ABCB4 protein synthesis within exon 12..."

However, Cullen et al. (2014) "assessed ABCB4 1583_1584G, in a wider sample of dogs with GBM compared with age and breed-matched controls. ... No statistically significant association existed between ABCB4 1583_1584G and the presence of GBM for all dogs combined or for Shetland Sheepdogs alone." The authors concluded "that clinical use of a genetic test for ABCB4 1583_1584G is premature and would not yet provide useful diagnostic information for veterinarians. It would also not provide dog breeders with information necessary to make informed breeding decisions."

Clinical features: GBM is an extrahepatic disease characterised by abnormal, intraluminal accumulation of mucus or thickened bile within the gallbladder. GBM commonly predisposes the animal to secondary gallbladder rupture, systemic infection, and extrahepatic biliary duct obstruction. Therefore, serum biochemistry often shows increased liver enzymes (AST, ALT) indicative of liver damage, hyperbilirubinemia, and leucocytosis in haematology. Common non-specific clinical signs include vomiting, lethargy, abdominal pain, anorexia, icterus, tachypnoea, polyuria-polydipsia, pyrexia, diarrhoea, and abdominal distention (Smalle, Cahalane & Köster, 2015). Chronic GBM progressing to ruptured gallbladders often present with more severe clinical signs of marked abdominal pain, jaundice, and pyrexia (Jaffey et al., 2019). [IT thanks DVM student Jonathan Haw Cherng Chee, who provided the basis of this contribution in April 2022]

Pathology: Distended gallbladder filled with mucus or bile is commonly the gross pathological findings of GBM. On the thickened inner mucosal surface of the gallbladder, GBM often presents as diffused, abundant, variably sized cystic structures filled with copious amounts of tenacious viscoelastic mucin. Histopathologically, hyperplastic tall columnar epithelial cells with abundant apical cytoplasmic mucus interspersed with scants amounts of bile within the gallbladder wall and bile duct are common (Mealey et al., 2010). [IT thanks DVM student Jonathan Haw Cherng Chee, who provided the basis of this contribution in April 2022]

Breeds: Cairn Terrier, Cocker Spaniel, Miniature Schnauzer, Pomeranian, Shetland Sheepdog.

Associated gene: