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Veterinarian competency in genetics is vital for a meaningful application of the rapidly growing number of genetic tests available for animals. We evaluated the use of genetic tests in the daily veterinary practice and the competency of university-employed veterinarians in applying basic principles of genetics in a clinical setting through an electronic survey with 14 cases and 7 statements on genetics. Ninety-one non-geneticist veterinarians from two veterinary faculties in two different countries responded. Almost half of the participants apply genetic tests during their daily work, with frequencies varying between weekly and once a year. The most common indication to request a genetic test was diagnostic testing of clinically ill patients. Although 80% of the veterinarians communicated the result of a genetic test themselves, only 56% of them found it "very to rather easy" to find the correct test, and only 32% of them always felt competent to interpret the result of the test. The number of correctly answered questions varied widely, with median scores of 9/14 (range: 0-14) and 5/7 (range: 0-7) for the cases and statements, respectively. Most difficulties were seen with recognition of pedigree inheritance patterns, while veterinarians scored better in breeding advice and probability of disease estimations. Veterinarians scored best on questions related to autosomal recessive inheritance, followed by complex, autosomal dominant, X-linked recessive, and X-linked dominant inheritance. This study exposed pain points in veterinarians' knowledge and has led to the formulation of recommendations for future education and communication between laboratories, geneticists, and veterinarians.
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Educación en Veterinaria , Animales , UniversidadesRESUMEN
Veterinarian competency in genetics is vital for a meaningful application of the rapidly growing number of genetic tests available for animals. We evaluated the use of genetic tests in the daily veterinary practice and the competency of university-employed veterinarians in applying basic principles of genetics in a clinical setting through an electronic survey with 14 cases and 7 statements on genetics. Ninety-one non-geneticist veterinarians from two veterinary faculties in two different countries responded. Almost half of the participants apply genetic tests during their daily work, with frequencies varying between weekly and once a year. The most common indication to request a genetic test was diagnostic testing of clinically ill patients. Although 80% of the veterinarians communicated the result of a genetic test themselves, only 56% of them found it "very to rather easy" to find the correct test, and only 32% of them always felt competent to interpret the result of the test. The number of correctly answered questions varied widely, with median scores of 9/14 (range 0-14) and 5/7 (range 0-7) for the cases and statements, respectively. Most difficulties were seen with recognition of pedigree inheritance patterns, while veterinarians scored better in breeding advice and probability of disease estimations. Veterinarians scored best on questions related to autosomal recessive inheritance, followed by complex, autosomal dominant, X-linked recessive, and X-linked dominant inheritance. This study exposed pain points in veterinarians' knowledge and has led to the formulation of recommendations for future education and communication between laboratories, geneticists, and veterinarians.
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Hepatitis E virus (HEV) as an emerging zoonotic pathogen causes a major public health issue. Transmission from domestic, wildlife and zoo animals to human has been widely reported. Whether pets also serve as reservoirs remains an intriguing question. In this study, we found the sero-positive rates of HEV-specific antibodies in pet dogs, cats and horses of 18.52% (30/162), 14.89% (7/47) and 18.18% (4/22) in the Netherlands. Although HEV viral RNA was not detected in these animals, we have demonstrated that dog liver cells are susceptible to HEV infection in vitro. These results call more attention to address the potential role of pets in the zoonotic transmission of HEV.
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Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.
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Genoma , Anotación de Secuencia Molecular/métodos , ARN Largo no Codificante/genética , Programas Informáticos , Transcriptoma , Animales , Benchmarking , Árboles de Decisión , Perros , Regulación de la Expresión Génica , Humanos , Ratones , Anotación de Secuencia Molecular/estadística & datos numéricos , Sistemas de Lectura Abierta , ARN Largo no Codificante/clasificación , ARN Largo no Codificante/metabolismo , ARN Mensajero/clasificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ARNRESUMEN
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.
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Cobre/metabolismo , Modelos Animales de Enfermedad , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/metabolismo , Animales , Terapia por Quelación , Mapeo Cromosómico , Dietoterapia , Perros , Estudios de Asociación Genética , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/metabolismo , Degeneración Hepatolenticular/terapia , Homeostasis , Humanos , Errores Innatos del Metabolismo de los Metales/terapia , Trasplante de ÓrganosRESUMEN
Introduction: Syringomyelia (SM) is a heritable disorder causing a fluid filled cavity (FFC) in the spinal cord with a reported overall prevalence of 39 to 46% in the Cavalier King Charles Spaniels (CKCS). Breeders started screening their CKCS with MRI in the Netherlands since 2004 and in Denmark since 2015. The goal of this study was to evaluate the effect of MRI-based selection in breeding on the prevalence of SM. Method: MRI scans of 2,125 purebred CKCS were available. SM was defined as having a visible FFC in the spinal cord. The prevalence of SM per year of birth was calculated, and a logistic regression was used to evaluate the affected status of offspring from affected versus unaffected parents and age category of the parent and study the combined effect of parental status and age-category to evaluate the effect on the affected status of the offspring. Results: The mean FFC in affected CKCS was 2.03 ± 1.47 mm and ranged from 0.5 to 9 mm (median of 1.5 mm). An age effect exists as older CKCS, which has a higher frequency of being affected compared with younger CKCS. There was no significant sex predilection for SM in this dataset. The mean prevalence of SM decreased slightly from 38% (2010-2014; 2.8 ± 1.3 years of age (mean ± sd); median 2.6 years) to 27% (2015-2019; 2.4 ± 1.2 years of age; median 2.1 years) in the screened population of CKCS (p = 4.3e-07). Breeding with two affected parents increased the odds ratio with 3.08 for producing affected offspring (95% CI 1.58-6.04) compared with breeding with unaffected parents. Discussion: MRI-based screening and selection against SM led to a minimal decrease in the prevalence of SM in the Dutch and Danish CKCS population. Breeding with dogs with SM significantly increases the risk of affected offspring. As the disorder is progressive with age, and based on the results of this study, MRI-based screening for all CKCS is recommended at an age of 3 years or older, and to reduce SM more effectively, CKCS affected with SM should not be used for breeding.
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Haemangiosarcoma is a relatively common malignant tumour in dogs, and one of the primary outcomes of interest for the Golden Retriever Lifetime Study. This study collects longitudinal data and samples from a cohort of golden retrievers, with the aim of identification of nutritional, genetic, environmental, lifestyle and reproductive risk factors for cancers and other important diseases in dogs. This analysis describes the accumulating data and samples, which are available for use by researchers to fulfil the study's objectives. As of September 2022, 233/3044 dogs enrolled in the study had been diagnosed with haemangiosarcoma (7.65%), with an incidence rate of 1.10 cases per 100 dog-years. Visceral haemangiosarcoma was the most common, affecting 211/3044 study dogs (6.9%). One hundred and twenty eight visceral haemangiosarcoma diagnoses specified the presence of splenic tumours (60.7%) and 119 specified the presence of cardiac tumours (56.4%). The probability of remaining without a haemangiosarcoma diagnosis declined from 100% from approximately 4 years of age, to a 12 year probability of 91.1% in intact females (95% CI 84.4%-98.3%), 60.7% in neutered females (95% CI 41.6%-88.6%), 72.9% in intact males (95% CI 62.9%-84.6%) and 70.0% in neutered males (95% CI 53.4%-92.0%). The 1 year survival probability for visceral haemangiosarcoma was 1.42% (95% CI 0.37%-5.47%); for cutaneous haemangiosarcoma, it was 84.6% (95% CI 67.1%-99.99%). The accumulated data and samples are a considerable resource for further investigation of canine haemangiosarcoma and have a potential role in translational medicine.
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Enfermedades de los Perros , Neoplasias Cardíacas , Hemangiosarcoma , Neoplasias Cutáneas , Neoplasias del Bazo , Humanos , Masculino , Femenino , Perros , Animales , Enfermedades de los Perros/patología , Hemangiosarcoma/epidemiología , Hemangiosarcoma/veterinaria , Neoplasias Cutáneas/veterinaria , Neoplasias Cardíacas/veterinaria , Neoplasias del Bazo/epidemiología , Neoplasias del Bazo/veterinariaRESUMEN
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.
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OBJECTIVE: To identify prognostic indicators and inflammatory markers associated with nonsurvival in dogs with gallbladder mucoceles (GBMs) following cholecystectomy and to evaluate C-reactive protein (CRP) and haptoglobin concentrations in dogs with GBMs compared to healthy controls. ANIMALS: 25 dogs that underwent cholecystectomy for removal of GBM and 20 healthy control dogs. METHODS: A prospective, multicenter cohort study. Survival outcomes to hospital discharge and 2 weeks postdischarge were recorded from medical records. Laboratory variables, inflammatory markers (CRP and haptoglobin), and 25-hydroxyvitamin(OH) D (25[OH]D) concentrations were measured preoperatively. Associations between signalment, clinicopathologic variables, acute patient physiologic and laboratory evaluation (APPLEFAST) scores, inflammatory markers, 25(OH)D concentration, and survival were analyzed using logistic regression. RESULTS: 76% (19/25) and 68% (17/25) of dogs survived to hospital discharge and 2 weeks postdischarge, respectively. For each additional year of age, the odds of nonsurvival in hospital and 2 weeks postdischarge increased by 2.2 (P = .01; 95% CI, 1.2 to 5.0) and 1.7 (P = .04; 95% CI, 1.0 to 3.2), respectively. Intraoperative systolic blood pressure ≤ 65 mm Hg increased the probability of nonsurvival in hospital (P < .04). Gallbladder perforation, APPLEFAST scores, and preoperative serum concentrations of CRP, haptoglobin, and 25(OH)D were not associated with survival. Serum CRP and haptoglobin concentrations were greater in dogs with GBM compared to controls (P < .001). CLINICAL RELEVANCE: Increasing age and intraoperative systolic blood pressure ≤ 65 mm Hg were associated with nonsurvival in dogs with GBM undergoing cholecystectomy. Serum CRP, haptoglobin, and 25(OH)D were not associated with nonsurvival postcholecystectomy in this sample population.
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Enfermedades de los Perros , Enfermedades de la Vesícula Biliar , Hipotensión , Mucocele , Animales , Perros , Cuidados Posteriores , Colecistectomía/veterinaria , Estudios de Cohortes , Enfermedades de los Perros/patología , Enfermedades de la Vesícula Biliar/cirugía , Enfermedades de la Vesícula Biliar/veterinaria , Haptoglobinas , Hipotensión/veterinaria , Mucocele/cirugía , Mucocele/veterinaria , Alta del Paciente , Estudios ProspectivosRESUMEN
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.
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Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered. Genetic studies in the Bedlington terrier, a dog breed affected with copper toxicosis, identified COMMD1, a gene that was previously unknown to be involved in copper metabolism. Besides the Bedlington terrier, a number of other dog breeds suffer from hereditary copper toxicosis and show similar phenotypes to humans with copper storage disorders. Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases. This article reviews the work that has been done on the Bedlington terrier, summarizes what was learned from studies into COMMD1 function, describes hereditary copper toxicosis phenotypes in other dog breeds, and discusses the opportunities for genome-wide association studies on copper toxicosis in the dog to contribute to the understanding of mammalian copper metabolism and copper metabolism disorders in man.
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Cobre/metabolismo , Degeneración Hepatolenticular/genética , Errores Innatos del Metabolismo de los Metales/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cobre/toxicidad , Modelos Animales de Enfermedad , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Perros , Degeneración Hepatolenticular/metabolismo , Humanos , Errores Innatos del Metabolismo de los Metales/metabolismo , Errores Innatos del Metabolismo de los Metales/veterinaria , MutaciónRESUMEN
BACKGROUND: An ectopic ureter is a congenital malformation characterized by caudal displacement of one or both ureteral orifices and is the most common cause of urinary incontinence in young dogs. Complete resolution of incontinence after surgery has been reported in 25-82% of dogs. The aim of this study was to identify preoperative prognostic factors for continence after surgical treatment of dogs with an ectopic ureter. Dogs were included if surgical correction of an ectopic ureter was performed and at least 1 year follow-up was available. RESULTS: Fifty-one dogs met the inclusion criteria. The ectopic ureters were either intramural (91%) or extramural (9%). The ectopic ureters were bilateral in 49% of cases. Overall median follow-up time after surgery was 6.5 years (range 1-13 years). Surgical correction alone resolved urinary incontinence in 47% of cases. Low grade pre-operative incontinence, male sex and pre-operative presence of ureteral or renal pyelum dilation were significantly associated with urinary continence after surgery. CONCLUSIONS: Dogs with severe preoperative incontinence were less likely to become completely continent after surgery, whereas male sex and preoperative dilation of the ureter or renal pyelum were positive prognostic indicators for continence. These results may assist in predicting outcome after surgical correction of ectopic ureters and suggest assessment of pre-operative urethral pressure profiling in future studies.
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Enfermedades de los Perros , Uréter , Incontinencia Urinaria , Perros , Masculino , Animales , Uréter/cirugía , Uréter/anomalías , Estudios de Seguimiento , Pronóstico , Enfermedades de los Perros/cirugía , Enfermedades de los Perros/etiología , Incontinencia Urinaria/etiología , Incontinencia Urinaria/cirugía , Incontinencia Urinaria/veterinariaRESUMEN
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.
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Cardiac disease is a leading cause of death for both humans and dogs. Genetic cardiomyopathies, including dilated cardiomyopathy (DCM), account for a proportion of these cases in both species. Patients may suffer from ventricular enlargement and systolic dysfunction resulting in congestive heart failure and ventricular arrhythmias with high risk for sudden cardiac death. Although canine DCM has similar disease progression and subtypes as in humans, only a few candidate genes have been found to be associated with DCM while the genetic background of human DCM has been more thoroughly studied. Additionally, experimental disease models using induced pluripotent stem cells have been widely adopted in the study of human genetic cardiomyopathy but have not yet been fully adapted for the in-depth study of canine genetic cardiomyopathies. The clinical presentation of DCM is extremely heterogeneous for both species with differences occurring based on sex predisposition, age of onset, and the rate of disease progression. Both genetic predisposition and environmental factors play a role in disease development which are identical in dogs and humans in contrast to other experimental animals. Interestingly, different dog breeds have been shown to develop distinct DCM phenotypes, and this presents a unique opportunity for modeling as there are multiple breed-specific models for DCM with less genetic variance than human DCM. A better understanding of DCM in dogs has the potential for improved selection for breeding and could lead to better overall care and treatment for human and canine DCM patients. At the same time, progress in research made for human DCM can have a positive impact on the care given to dogs affected by DCM. Therefore, this review will analyze the feasibility of canines as a naturally occurring bidirectional disease model for DCM in both species. The histopathology of the myocardium in canine DCM will be evaluated in three different breeds compared to control tissue, and the known genetics that contributes to both canine and human DCM will be summarized. Lastly, the prospect of canine iPSCs as a novel method to uncover the contributions of genetic variants to the pathogenesis of canine DCM will be introduced along with the applications for disease modeling and treatment.
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[This corrects the article DOI: 10.1371/journal.pone.0244102.].
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Copper toxicosis is a major cause of hepatitis in dogs. We have shown that variants in ATP7A and ATP7B modulate hepatic copper levels in Labrador retrievers and Dobermans. However, these variants cannot fully explain the observed variation in hepatic copper levels in these dog breeds. Homozygous deletion of exon 2 of COMMD1 causes copper toxicosis in Bedlington terriers. We investigated the possible involvement of COMMD1 in the multifactorial aetiology of copper toxicosis in Labrador retrievers and Dobermans. Thirty dogs of each breed with known hepatic copper status were selected for DNA sequence analysis of the three exons and flanking intronic regions of COMMD1. The observed variants were tested for association with hepatic copper levels by linear model analysis. Several variants were observed in the DNA sequence of COMMD1 in both Labrador retrievers (nine variants) and Dobermans (11 variants) but none of these was associated with variations of hepatic copper concentrations. We conclude that COMMD1 did not play a major role in the aetiology of copper associated hepatitis in Labrador retrievers and Dobermans.
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Proteínas Adaptadoras Transductoras de Señales/genética , Cobre/toxicidad , Enfermedades de los Perros/genética , Hepatopatías/veterinaria , Animales , Secuencia de Bases , Cobre/metabolismo , Perros , Exones/genética , Variación Genética/genética , Hepatitis Animal/inducido químicamente , Hepatitis Animal/genética , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/veterinaria , Hepatopatías/etiología , Hepatopatías/genética , Especificidad de la EspecieRESUMEN
Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Gallbladder hypokinesia has been proposed to contribute to its formation and progression. The specific cause of gallbladder stasis in dogs with GBM as well as viable treatment options to resolve dysmotility remains unknown. Vitamin D deficiency is one of the many potential causes of gallbladder hypokinesia in humans and repletion results in complete resolution of stasis. Improving our understanding of the relationship between serum vitamin D and GBM could help identify dogs as a model for humans with gallbladder hypokinesia. Furthermore, this relationship could provide insight into the pathogenesis of GBM and support the need for future studies to investigate vitamin D as a novel treatment target. Therefore, goals of this study were i) to determine if serum 25-hydroxyvitamin(OH)D concentrations were decreased in dogs with GBM, ii) if serum 25(OH)D concentrations were different in clinical versus dogs subclinical for GBM, and iii) to determine if serum 25(OH)D concentrations could predict the ultrasonographic type of GBM. Sixty-two dogs (clinical, n = 26; subclinical, n = 36) with GBM and 20 healthy control dogs were included in this prospective observational study. Serum 25(OH)D concentrations were measured with a competitive chemiluminescence immunoassay. Overall, dogs with GBM had lower serum 25(OH)D concentrations than control dogs (P = 0.004). Subsequent subgroup analysis indicated that this difference was only significant in the subclinical group compared to the control dogs (P = 0.008), and serum 25(OH)D concentrations did not significantly differ between dogs clinical for GBM versus subclinical or control dogs, indicating that inflammatory state in clinical dogs was not the major constituent of the observed findings. Decreasing serum 25(OH)D concentrations, but not clinical status, was associated with a more advanced developmental stage of GBM type determined by ultrasonography. Our results indicate that vitamin D has a role in dogs with GBM. Additional studies are needed to assess if reduced vitamin D in dogs with GBM is a cause or effect of their biliary disease and to investigate if vitamin D supplementation could be beneficial for dogs with GBM.
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Enfermedades de los Perros/sangre , Enfermedades de la Vesícula Biliar/sangre , Mucocele/sangre , Vitamina D/análogos & derivados , Animales , Perros , Femenino , Enfermedades de la Vesícula Biliar/veterinaria , Masculino , Mucocele/veterinaria , Vitamina D/sangreRESUMEN
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.
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BACKGROUND: Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS. RESULTS: The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans. CONCLUSION: A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.
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Neoplasias Óseas/genética , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Osteosarcoma/genética , Animales , Neoplasias Óseas/patología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Perros , Femenino , Redes Reguladoras de Genes , Humanos , Estimación de Kaplan-Meier , Masculino , Modelos Genéticos , Osteosarcoma/patología , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Wilson Disease is a rare autosomal recessive liver disorder in humans. Although its clinical presentation and age of onset are highly variable, hallmarks include signs of liver disease, neurological features and so-called Kayser-Fleischer rings in the eyes of the patient. Hepatic copper accumulation leads to liver disease and eventually to liver cirrhosis. Treatment options include life-long copper chelation therapy and/or decrease in copper intake. Eventually liver transplantations are indicated. Although clinical outcome of liver transplantations is favorable, the lack of suitable donor livers hampers large numbers of transplantations. As an alternative, cell therapies with hepatocytes or liver stem cells are currently under investigation. Stem cell biology in relation to pets is in its infancy. Due to the specific population structure of dogs, canine copper toxicosis is frequently encountered in various dog breeds. Since the histology and clinical presentation resemble Wilson Disease, we combined genetics, gene-editing, and matrices-based stem cell cultures to develop a translational preclinical transplantation model for inherited copper toxicosis in dogs. Here we describe the roadmap followed, starting from the discovery of a causative copper toxicosis mutation in a specific dog breed and culminating in transplantation of genetically-engineered autologous liver stem cells.