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  • 1
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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
    The Company of Biologists ; 2016
    In:  Disease Models & Mechanisms Vol. 9, No. 1 ( 2016-01-01), p. 25-38
    Details
    In: Disease Models & Mechanisms, The Company of Biologists, Vol. 9, No. 1 ( 2016-01-01), p. 25-38
    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.
    Type of Medium: Online Resource
    ISSN: 1754-8411 , 1754-8403
    URL: Article
    DOI: 10.1242/dmm.020263
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2016
    detail.hit.zdb_id: 2451104-3
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  • 2
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    Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs
    Wiley ; 2019
    In:  Journal of Veterinary Internal Medicine Vol. 33, No. 4 ( 2019-07), p. 1646-1652
    Details
    In: Journal of Veterinary Internal Medicine, Wiley, Vol. 33, No. 4 ( 2019-07), p. 1646-1652
    Abstract: Hepatic copper accumulation causes chronic hepatitis in dogs. Mutations in the copper transporters ATP7A and ATP7B were, respectively, associated with attenuation and enhancement of hepatic copper concentrations in Labrador Retrievers. There is a predisposition of Dobermanns to hepatitis with increased hepatic copper concentrations. Objectives To investigate whether the ATP7A :c.980C 〉 T and ATP7B :c.4358G 〉 A mutations identified in Labrador Retrievers were associated with hepatic copper concentrations in Dobermanns. Animals Dobermanns from the Netherlands (n = 122) and the United States (n = 78). Methods In this retrospective study, mutations in ATP7A and ATP7B were investigated as risk factors for hepatic copper accumulation in Dobermanns. Liver biopsies of 200 Dobermanns were evaluated by histochemical copper staining, quantitative copper measurement, or both modalities. ATP7A and ATP7B genotypes were obtained by Kompetitive Allele Specific PCR. A linear regression model was used to investigate an association between genotype and hepatic copper concentrations. Results The ATP7A :c.980C 〉 T was identified in both Dutch (2 heterozygous individuals) and American Dobermanns. In the American cohort, the minor allele frequency of the mutation was low (.081) and a possible effect on hepatic copper concentrations could not be established from this data set. A significant association of the ATP7B :c.4358G 〉 A variant with increased hepatic copper concentrations in Dobermanns was observed. Conclusions and Clinical Importance The ATP7B :c.4358G 〉 A variant could be a contributor to hepatic copper accumulation underlying the risk of development of copper‐associated hepatitis in breeds other than the Labrador Retriever.
    Type of Medium: Online Resource
    ISSN: 0891-6640 , 1939-1676
    URL: Issue
    URL: Article
    DOI: 10.1111/jvim.2019.33.issue-4
    DOI: 10.1111/jvim.15536
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2177690-8
    SSG: 22
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  • 3
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    The Histopathological Characteristic of Gastric Carcinoma in the Belgian Tervueren and Groenendael Dog: A Comparison of Two Classification Methods
    MDPI AG ; 2023
    In:  Animals Vol. 13, No. 9 ( 2023-05-03), p. 1532-
    Details
    In: Animals, MDPI AG, Vol. 13, No. 9 ( 2023-05-03), p. 1532-
    Abstract: Gastric carcinoma is generally considered to be a rare disease in dogs, carrying a grave prognosis. However, in the Tervueren and Groenendael varieties of the Belgian Shepherd dog breed, the disease is highly prevalent. While histopathology is the gold standard for diagnosing gastric carcinoma, there is no general consensus on the methods for histological classification in these cases. Biopsies of a group of 61 dogs with confirmed gastric carcinoma (45 Tervueren and 16 Groenendael) were examined and classified according to World Health Organization (WHO) and Laurén classifications. Kaplan–Meier curves were used to compare survival between the different subtypes and simple and multiple linear regression were used to analyse the association between age of onset and breed variant, sex, neuter status, location of the tumour, inflammation score, and Laurén and WHO classifications. Mean age at diagnosis was significantly different in Groenendael (10.1 ± 2.01) and Tervueren dogs (8.5 ± 1.90). The Laurén classification resulted in 29 (48%) diffuse- and 32 (52%) intestinal-type tumours. Applying the WHO classification resulted in 30 (49%) tubular carcinoma growth patterns and 31 (51%) others. Median survival time was significantly reduced for the diffuse type as compared to the intestinal type according to the Laurén classification, with the same median survival time results for tubular compared to non-tubular subtypes according to the WHO classification (median survival time of 61 vs. 182 days, respectively). Using the WHO and Lauren classification on tumour biopsies may help the practising clinician in the prognostication of gastric carcinoma in Tervueren and Groenendael dogs.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani13091532
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 4
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    An Inflammatory Myopathy in the Dutch Kooiker Dog
    MDPI AG ; 2023
    In:  Animals Vol. 13, No. 9 ( 2023-04-29), p. 1508-
    Details
    In: Animals, MDPI AG, Vol. 13, No. 9 ( 2023-04-29), p. 1508-
    Abstract: The Dutch Kooiker dog (het Nederlandse Kooikerhondje) is one of nine Dutch dog breeds. As of 1960, a number of heritable diseases have been noted in this breed. One is an inflammatory myopathy that emerged in 1972, with numbers of affected dogs gradually increasing during the last few decades. The objective of this paper is to describe clinical signs, laboratory results, electromyography and histopathology of the muscle biopsies of the affected dogs. Method: Both retrospectively as well as prospectively affected Kooiker dogs were identified and categorized using a Tiered level of Confidence. Results: In total, 160 Kooiker dogs—40 Tier I, 33 Tier II and 87 Tier III—were included. Clinical signs were (1) locomotory problems, such as inability to walk long distances, difficulty getting up, stiff gait, walking on eggshells; (2) dysphagia signs such as drooling, difficulty eating and/or drinking; or (3) combinations of locomotory and dysphagia signs. CK activities were elevated in all except for one dog. Histopathology revealed a predominant lymphohistiocytic myositis with a usually low and variable number of eosinophils, neutrophils and plasma cells. It is concluded that, within this breed, a most likely heritable inflammatory myopathy occurs. Further studies are needed to classify this inflammatory myopathy, discuss its treatment, and unravel the genetic cause of this disease to eradicate it from this population.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani13091508
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 5
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    Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers
    MDPI AG ; 2020
    In:  Life Vol. 10, No. 11 ( 2020-10-31), p. 266-
    Details
    In: Life, MDPI AG, Vol. 10, No. 11 ( 2020-10-31), p. 266-
    Abstract: Copper toxicosis is a complex genetic disorder in Labrador retrievers characterized by hepatic copper accumulation eventually leading to liver cirrhosis. The variation of hepatic copper levels in Labrador retrievers has been partly explained by mutations in ATP7A c.980C 〉 T and ATP7B c.4358G 〉 A. To further elucidate the genetic background of this disease, we used targeted Next Generation Sequencing (NGS) in a cohort of 95 Labrador retrievers to analyze 72 potential modifier genes for variations associated with hepatic copper levels. Variants associated with copper levels were subsequently evaluated in a replication cohort of 144 Labrador retrievers. A total of 44 variants in 25 different genes were identified, of which four showed significant association with copper levels. Of the four variants found associated with hepatic copper levels in the NGS cohort, one was validated in the replication cohort. The non-reference allele of the variant NC_006602.3.g.52434480C 〉 T in RETN resulting in amino-acid change p.Leu7Phe was associated with decreased hepatic copper levels. In humans, resistin is associated with severity of non-alcoholic fatty liver disease, fibrosis, cirrhosis and mitochondrial dysfunction in hepatocytes. Further studies are needed to investigate the biological function of RETN p.Leu7Phe in the development of copper toxicosis in Labrador retrievers.
    Type of Medium: Online Resource
    ISSN: 2075-1729
    URL: Article
    DOI: 10.3390/life10110266
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662250-6
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  • 6
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    Canine models of copper toxicosis for understanding mammalian copper metabolism
    Springer Science and Business Media LLC ; 2012
    In:  Mammalian Genome Vol. 23, No. 1-2 ( 2012-2), p. 62-75
    Details
    In: Mammalian Genome, Springer Science and Business Media LLC, Vol. 23, No. 1-2 ( 2012-2), p. 62-75
    Type of Medium: Online Resource
    ISSN: 0938-8990 , 1432-1777
    URL: Article
    DOI: 10.1007/s00335-011-9378-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 1459397-X
    SSG: 12
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  • 7
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    Prevalence of Echocardiographic Evidence of Trace Mitral and Aortic Valve Regurgitation in 50 Clinically Healthy, Young Adult Labrador Retrievers without Heart Murmur
    MDPI AG ; 2022
    In:  Animals Vol. 12, No. 18 ( 2022-09-16), p. 2442-
    Details
    In: Animals, MDPI AG, Vol. 12, No. 18 ( 2022-09-16), p. 2442-
    Abstract: Background—Though physiologic regurgitation of the right-sided cardiac valves is well recognized in dogs and other mammals, the prevalence of trace insufficiency of the mitral and aortic valves in clinically healthy, young adult dogs is unknown. Methods—In this observational cross-sectional study, 50 clinically healthy, young adult Labrador retrievers without an audible heart murmur were enrolled. All dogs were bred and owned by a single organization. Cardiac screening was requested for all dogs that were intended for breeding. These dogs underwent a cardiac auscultation and transthoracic echocardiography by a veterinary cardiology specialist. If mitral or aortic valve regurgitation was noticed, the jet size was subjectively assessed on color Doppler echocardiography. Pedigree analysis was performed to reveal a possible hereditary background of mitral valve regurgitation. Results—The prevalence of trivial mitral valve regurgitation was 52% with no significant predisposition to gender (p = 0.86) or haircoat color (p = 0.68). The prevalence of aortic valve regurgitation was 4%. Pedigree analysis for mitral valve regurgitation showed familial clustering, suggesting a hereditary background of the trait. Conclusions—The prevalence of silent trace mitral valve regurgitation in young adult Labrador retrievers was high. Because the regurgitant jet was trivial in all dogs, it is probably physiologic.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani12182442
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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