In other species: dog , pig , taurine cattle , sheep

Categories: Liver/biliary system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 277900 (trait) , 606882 (gene)

Links to MONDO diseases:

• MONDO:0010200: Wilson disease

Mendelian trait/disorder: yes

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: A disorder of copper metabolism, due to a deficiency of ceruloplasmin, which forms a complex with copper. The excess copper is deposited in the brain (causing mental retardation) or the liver (causing jaundice and cirrhosis).

Molecular basis: Noting the similarity of the clinical signs of a single "crossbred" cat (described in Clinical features section) to Wilson disease in humans, Asada et al. (2019) sequenced comparative functional genes in the affected cat and identified the variant c.3890C>G (p. T1297R) of the ATP7B gene as being likely causal. The authors reported that "the patient and its littermate had a single‐nucleotide variation (SNV, p. T1297R) that impaired the function of the ATP7B gene product; the gene that is mutated in patients with Wilson's disease (WD). Hepatic copper accumulation was believed to be associated with the SNV of the ATP7B gene, and the patient had a genetic disorder of copper metabolism equivalent to WD in humans." Asada et al. identified a second likely causal variant ATP7B in 2020: "Upon sequence analysis of genomic DNA samples obtained from the five cats with HCA [hepatic copper accumulation] ... p.T1297R and p.P550L were predicted to have high functional effects. The latter was common in two cats (cases 2 and 4). All SNVs identified herein were homozygous. The region containing p.T1297R was within the copper-transporting P-type ATPase domain and that containing p.P550L was within the copper-binding domain." Recchia et al. (2023) investigated a 2-year-old domestic longhair cat with a primary copper hepatopathy (PCH): "Sanger sequencing of the cat’s ATP7B gene, which encodes a copper-transporting protein, revealed a novel, ‘likely pathogenic’, single nucleotide variation (c.3670t/a [p.Trp1224Arg]), for which the cat is heterozygous. ... The cat is ... the first reported with PCH and a ‘likely pathogenic’ heterozygous ATP7B genotype, which suggests that normal ATP7B alleles could be recessive to or incompletely/co- dominant with deleterious ATP7B alleles in cats, as has been reported in other species."

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

Clinical features: Asada et al. (2019): "A 9‐month‐old intact crossbred female cat was presented with jaundice, intermittent anorexia and lethargy, increased hepatic enzyme activities, and hyperammonemia. Abdominal ultrasound and computed tomographic examinations determined that the liver had a rounded and irregular margin, and histopathological examination identified excessive accumulation of copper hepatocytes in the liver. Concentrations of both blood and urine copper were higher than in healthy cats."

Prevalence: In a survey of 54 cats for whom "intraoperative liver tissue specimens" were available, Asada et al. (2020) reported 4 with "hepatic copper accumulation (HCA)", three of which had "single-nucleotide variations in ATP7B".

Associated gene: