title: Copper toxicosis in non-COMMD1 Bedlington terriers is associated with metal transport gene ABCA12.
abstract: Wilson's disease, caused by a mutation in the ATP-ase 7B gene, is the only genetically characterised human disease with inhibition of biliary copper excretion and toxic copper accumulation in liver and occasionally brain. A similar copper toxicosis occurs in Bedlington terriers (CT) with liver damage only. Although CT has been associated with a defect in the COMMD1 gene (COMMD1 (del/del)), Bedlington terriers with CT and lacking this mutation are also recognised (non-COMMD1 (del/del)). A study was designed to identify any other gene polymorphisms associated with copper toxicity in Bedlington terriers employing genome wide association studies (GWAS) followed by deep sequencing of the candidate region. Blood for DNA analysis and liver for confirmation of the diagnosis was obtained from 30 non-COMMD1 (del/del) Bedlington terriers comprising equal numbers of CT-affected dogs and controls. DNA was initially subjected to GWAS screening and then further sequencing to target the putative mutant gene. The study has identified a significant disease association with a region on chromosome 37 containing identified SNP's which are highly significantly associated with non-COMMD1 (del/del) Bedlington terrier CT. This region contains the ABCA12 gene which bears a close functional relationship to ATP-ase 7B responsible for Wilson's disease in man.
authors.affiliation: Institute of Infection and Global Health, School of Veterinary Science, University of Liverpool, ic2 Science Park, Brownlow Hill, Liverpool L3 5RF, United Kingdom. Electronic address: shaywood@liverpool.ac.uk.
authors.forename: Susan
authors.initials: S
authors.lastname: Haywood
authors.affiliation: Canine Genetics, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Boursnell
authors.affiliation: Clinical Engineering, Institute of Ageing and Chronic Disease, Faculty of Health & Life Science, University of Liverpool, Liverpool L69 3G, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Loughran
authors.affiliation: Institute of Infection and Global Health, School of Veterinary Science, University of Liverpool, ic2 Science Park, Brownlow Hill, Liverpool L3 5RF, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Trafford
authors.affiliation: Institute of Infection and Global Health, School of Veterinary Science, University of Liverpool, ic2 Science Park, Brownlow Hill, Liverpool L3 5RF, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Isherwood
authors.affiliation: Centre for Genomics Research, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Centre for Genomics Research, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Olohan
authors.affiliation: Institute of Infection and Global Health, School of Veterinary Science, University of Liverpool, ic2 Science Park, Brownlow Hill, Liverpool L3 5RF, United Kingdom.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Carter
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D003300:Copper / Q000633:toxicity*; D004285:Dogs; D055106:Genome-Wide Association Study; D007438:Introns / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D003300:Copper
keywords: ABCA12 gene; Bedlington terriers; COMMD1 gene; Copper toxicosis; Wilson’s disease