The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders
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...
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| Format: | Article |
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The Company of Biologists
2016-01-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/9/1/25 |
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| author | Hille Fieten Yadvinder Gill Alan J. Martin Mafalda Concilli Karen Dirksen Frank G. van Steenbeek Bart Spee Ted S. G. A. M. van den Ingh Ellen C. C. P. Martens Paola Festa Giancarlo Chesi Bart van de Sluis Roderick H. J. H. Houwen Adrian L. Watson Yurii S. Aulchenko Victoria L. Hodgkinson Sha Zhu Michael J. Petris Roman S. Polishchuk Peter A. J. Leegwater Jan Rothuizen |
| author_facet | Hille Fieten Yadvinder Gill Alan J. Martin Mafalda Concilli Karen Dirksen Frank G. van Steenbeek Bart Spee Ted S. G. A. M. van den Ingh Ellen C. C. P. Martens Paola Festa Giancarlo Chesi Bart van de Sluis Roderick H. J. H. Houwen Adrian L. Watson Yurii S. Aulchenko Victoria L. Hodgkinson Sha Zhu Michael J. Petris Roman S. Polishchuk Peter A. J. Leegwater Jan Rothuizen |
| author_sort | Hille Fieten |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T19:29:53Z |
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| id | doaj.art-ed1cab5637da4a468e9d141775e641c2 |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-23T19:29:53Z |
| publishDate | 2016-01-01 |
| publisher | The Company of Biologists |
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| series | Disease Models & Mechanisms |
| spelling | doaj.art-ed1cab5637da4a468e9d141775e641c22022-12-21T17:33:57ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032016-01-0191253810.1242/dmm.020263020263The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disordersHille Fieten0Yadvinder Gill1Alan J. Martin2Mafalda Concilli3Karen Dirksen4Frank G. van Steenbeek5Bart Spee6Ted S. G. A. M. van den Ingh7Ellen C. C. P. Martens8Paola Festa9Giancarlo Chesi10Bart van de Sluis11Roderick H. J. H. Houwen12Adrian L. Watson13Yurii S. Aulchenko14Victoria L. Hodgkinson15Sha Zhu16Michael J. Petris17Roman S. Polishchuk18Peter A. J. Leegwater19Jan Rothuizen20 Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands 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 Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA Department of Biochemistry, 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 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.http://dmm.biologists.org/content/9/1/25ATP7AATP7BDogLiver |
| spellingShingle | Hille Fieten Yadvinder Gill Alan J. Martin Mafalda Concilli Karen Dirksen Frank G. van Steenbeek Bart Spee Ted S. G. A. M. van den Ingh Ellen C. C. P. Martens Paola Festa Giancarlo Chesi Bart van de Sluis Roderick H. J. H. Houwen Adrian L. Watson Yurii S. Aulchenko Victoria L. Hodgkinson Sha Zhu Michael J. Petris Roman S. Polishchuk Peter A. J. Leegwater Jan Rothuizen The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders Disease Models & Mechanisms ATP7A ATP7B Dog Liver |
| title | The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders |
| title_full | The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders |
| title_fullStr | The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders |
| title_full_unstemmed | The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders |
| title_short | The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders |
| title_sort | menkes and wilson disease genes counteract in copper toxicosis in labrador retrievers a new canine model for copper metabolism disorders |
| topic | ATP7A ATP7B Dog Liver |
| url | http://dmm.biologists.org/content/9/1/25 |
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