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The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders.
Dis Model Mech. 2016 Jan; 9(1):25-38.DM

Abstract

The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.

Authors+Show Affiliations

Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands h.fieten@uu.nl.The WALTHAM Centre for Pet Nutrition, Waltham-on-the-Wolds, Melton Mowbray, Leicestershire, LE14 4RT, UK.The WALTHAM Centre for Pet Nutrition, Waltham-on-the-Wolds, Melton Mowbray, Leicestershire, LE14 4RT, UK.Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.TCCI Consultancy BV, Cicerolaan 1, 3584 AJ Utrecht, The Netherlands.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center, Lundlaan 6, 3584 EA Utrecht, The Netherlands.The WALTHAM Centre for Pet Nutrition, Waltham-on-the-Wolds, Melton Mowbray, Leicestershire, LE14 4RT, UK.Novosibirsk State University, 630090 Novosibirsk, Russia Institute of Cytology and Genetics, 630090 Novosibirsk, Russia.Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, USA.Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, USA.Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, USA Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26747866

Citation

Fieten, Hille, et al. "The Menkes and Wilson Disease Genes Counteract in Copper Toxicosis in Labrador Retrievers: a New Canine Model for Copper-metabolism Disorders." Disease Models & Mechanisms, vol. 9, no. 1, 2016, pp. 25-38.
Fieten H, Gill Y, Martin AJ, et al. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech. 2016;9(1):25-38.
Fieten, H., Gill, Y., Martin, A. J., Concilli, M., Dirksen, K., van Steenbeek, F. G., Spee, B., van den Ingh, T. S., Martens, E. C., Festa, P., Chesi, G., van de Sluis, B., Houwen, R. H., Watson, A. L., Aulchenko, Y. S., Hodgkinson, V. L., Zhu, S., Petris, M. J., Polishchuk, R. S., ... Rothuizen, J. (2016). The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Disease Models & Mechanisms, 9(1), 25-38. https://doi.org/10.1242/dmm.020263
Fieten H, et al. The Menkes and Wilson Disease Genes Counteract in Copper Toxicosis in Labrador Retrievers: a New Canine Model for Copper-metabolism Disorders. Dis Model Mech. 2016;9(1):25-38. PubMed PMID: 26747866.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. AU - Fieten,Hille, AU - Gill,Yadvinder, AU - Martin,Alan J, AU - Concilli,Mafalda, AU - Dirksen,Karen, AU - van Steenbeek,Frank G, AU - Spee,Bart, AU - van den Ingh,Ted S G A M, AU - Martens,Ellen C C P, AU - Festa,Paola, AU - Chesi,Giancarlo, AU - van de Sluis,Bart, AU - Houwen,Roderick H J H, AU - Watson,Adrian L, AU - Aulchenko,Yurii S, AU - Hodgkinson,Victoria L, AU - Zhu,Sha, AU - Petris,Michael J, AU - Polishchuk,Roman S, AU - Leegwater,Peter A J, AU - Rothuizen,Jan, PY - 2016/1/10/entrez PY - 2016/1/10/pubmed PY - 2016/10/19/medline KW - ATP7A KW - ATP7B KW - Dog KW - Liver SP - 25 EP - 38 JF - Disease models & mechanisms JO - Dis Model Mech VL - 9 IS - 1 N2 - The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy. SN - 1754-8411 UR - https://www.unboundmedicine.com/medline/citation/26747866/The_Menkes_and_Wilson_disease_genes_counteract_in_copper_toxicosis_in_Labrador_retrievers:_a_new_canine_model_for_copper_metabolism_disorders_ L2 - http://dmm.biologists.org/cgi/pmidlookup?view=long&pmid=26747866 DB - PRIME DP - Unbound Medicine ER -