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Mucocele formation in dogs is a unique and enigmatic muco-obstructive disease of the gallbladder caused by amassment of abnormal mucus that bears striking pathological similarity to cystic fibrosis. We investigated the role of CFTR in the pathogenesis of this disease. The location and frequency of disease-associated variants in the coding region of CFTR was compared using whole genome sequence data from 2,642 dogs representing breeds at low-risk, high-risk, or with confirmed disease. Expression, localization, and ion transport activity of CFTR was quantified in control and mucocele gallbladders by NanoString, Western blotting, immunofluorescence imaging, and studies in Ussing chambers. Our results establish significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. A significantly lower quantity of CFTR protein was demonstrated relative to E-cadherin in mucocele compared to control gallbladder mucosa. Immunofluorescence identified CFTR along the apical membrane of epithelial cells in control gallbladders but not in mucocele gallbladder epithelium. Decreases in mRNA copy number for CFTR was accompanied by decreases in mRNA for the Cl-/HCO3- exchanger SLC26A3, K+ channels (KCNQ1, KCNN4), and vasoactive intestinal polypeptide receptor (VIPR1) which suggest a driving force for change in secretory function of gallbladder epithelial cells in the pathogenesis of mucocele formation. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low risk, high risk, and definitively diagnosed groups of dogs. This study describes a unique, naturally occurring muco-obstructive disease of the canine gallbladder, with uncanny similarity to cystic fibrosis, and driven by underlying failure of CFTR function.
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A potential emerging shortage of veterinary medical educators requires the profession to acknowledge and understand the factors leading to this outcome. Expanding class sizes within existing schools and colleges of veterinary medicine and the expected expansion of new programs seeking AVMA-Council of Education accreditation have heightened the need to address an impending shortage of veterinary medical educators. A solution-oriented approach that accurately projects educator workforce needs and identifies factors contributing to the shortage requires effective collaboration across various partnering organizations to develop innovations in pedagogy and educational delivery methods. The veterinary profession must also identify and reduce disincentives that deter students and post-DVM trainees from pursuing careers in education. Finally, efforts at the state and federal level are critical to advocate for financial support and incentives for expansion of the veterinary medical educator workforce. Through these collective approaches and partnerships, the veterinary medical educator workforce can be strengthened to overcome obstacles for educating the next generation of veterinarians to meet societal needs.
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Educação em Veterinária , Médicos Veterinários , Médicos Veterinários/provisão & distribuição , Estados Unidos , Humanos , Faculdades de Medicina VeterináriaRESUMO
BACKGROUND: Chronic renin-angiotensin-aldosterone system (RAAS) activation is harmful. Amlodipine activates RAAS in humans and dogs, but contradictory data exist for systemically hypertensive (SHT) cats. HYPOTHESIS: Cats with SHT and chronic kidney disease treated with amlodipine (SHT/CKD-A) are RAAS activated. ANIMALS: Client-owned cats: unmedicated normotensive (NT) cats (n = 9); SHT/CKD-A cats (n = 5) with median systolic blood pressure of 170 mmHg (vs. 195 mmHg, pre-treatment), chronic kidney disease, and receiving no RAAS-suppressive therapy. METHODS: Serum was frozen (-80 °C) until RAAS analysis via equilibrium analysis. The RAAS variables (reported as median (minimum-maximum)) were compared between groups, using Mann-Whitney U test. RESULTS: Angiotensin 1, angiotensin 1,7, angiotensin III, and angiotensin 1,5, and angiotensin-converting enzyme (ACE)-2 activity were higher in SHT/CKD-A cats compared to NT cats, while ACE activity was lower in SHT/CKD-A cats compared to NT cats (p < 0.05 all). A marker for alternative RAAS influence (ALT-S) was significantly higher (69; 58-73 pmol/pmol) in SHT/CKD-A cats compared to NT cats (35; 14-63 pmol/pmol; p = 0.001). Aldosterone concentrations were significantly higher (393; 137-564 pmol/L) in SHT/CKD-A cats compared to NT cats (129; 28-206 pmol/L; p = 0.007). CONCLUSION AND CLINICAL IMPORTANCE: Circulating RAAS is activated in systemically hypertensive cats receiving amlodipine. Although this study did not parse out the individual contributions of SHT, chronic kidney disease, and amlodipine, the findings suggest that the use of concurrent RAAS-suppressant therapy, specifically aldosterone antagonism, in amlodipine-treated SHT cats with chronic kidney disease might be indicated.
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BACKGROUND: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. HYPOTHESIS: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. ANIMALS: Fifty-two privately owned CKCS with no or preclinical MMVD. METHODS: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. RESULTS: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 µM (P < .0001) and Vel at 0.03 µM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response. CONCLUSIONS AND CLINICAL IMPORTANCE: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.
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Doenças do Cão , Doenças das Valvas Cardíacas , Cães , Animais , Agregação Plaquetária , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Doenças do Cão/tratamento farmacológico , Doenças do Cão/genética , Doenças das Valvas Cardíacas/veterináriaRESUMO
BACKGROUND: Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease. HYPOTHESIS/OBJECTIVES: To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD. ANIMALS: Fifty-seven client-owned dogs with MMVD ACVIM Stage B2, C, or D and administered pimobendan to steady state blood concentrations. METHODS: Prospective, observational study. Samples were collected using a sparse-sampling protocol at specific intervals after administration of pimobendan. Plasma pimobendan and the active metabolite (O-desmethyl-pimobendan, ODMP) concentrations were determined via high-pressure liquid chromatography and fluorescence detection. Data was analyzed via a population pharmacokinetic approach and nonlinear mixed effects modeling (NLME). Numerous covariates were examined in the NLME model. RESULTS: The absorption and elimination half-lives (t1/2 ) were approximately 1.4 and 1 hour for pimobendan and 1.4 and 1.3 hours for ODMP, respectively. Pharmacokinetic parameters were highly variable, especially the values for pimobendan absorption and elimination rate, and absorption rate of ODMP with coefficients of variation of 147.84%, 64.51% and 64.49%, respectively. No covariate evaluated was a significant source of variability. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetic parameters were highly variable among this group of dogs with MMVD. The variability was not associated with the dog's age, body weight or condition score, stage of heart disease, dose, serum creatinine, or alkaline phosphatase.
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Doenças do Cão , Cardiopatias , Doenças das Valvas Cardíacas , Humanos , Cães , Animais , Valva Mitral , Estudos Prospectivos , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Cardiopatias/veterinária , Administração Oral , Doenças do Cão/tratamento farmacológicoRESUMO
BACKGROUND: Holter electrocardiographic monitoring is a cornerstone of diagnostic testing for arrhythmogenic cardiomyopathy (ACM) in Boxer dogs, but physical activity during monitoring is not controlled. In humans, exercise testing (ExT) can identify latent tachyarrhythmias associated with cardiomyopathy, and exercise increases serum cardiac troponin-I concentrations ([hs-cTnI]). These effects have not yet been investigated in Boxer dogs. HYPOTHESIS/OBJECTIVES: Subjecting Boxer dogs to brief, moderate-intensity ExT can identify changes in Holter recordings and [hs-cTnI] compared to baseline results. ANIMALS: Thirty overtly healthy, client-owned Boxer dogs. METHODS: Prospective interventional study. Dogs underwent baseline diagnostic testing including 24-hour Holter monitoring and [hs-cTnI], followed by brief ExT (accompanied, brisk stair-climbing and -descending for <5 minutes). RESULTS: Eleven dogs (37%) had >100 premature ventricular complexes (PVCs)/24 hours at baseline (3), ExT (3), or both (5). After ExT, these dogs had more PVCs/24 hours and greater increases in [hs-cTnI] compared to those with ≤100 PVCs/24 hours. Dogs with the striatin mutation had more PVCs/24 hours and a greater increase in [hs-cTnI] after ExT than did dogs without the striatin mutation. CONCLUSIONS AND CLINICAL IMPORTANCE: Exercise testing may improve the binary classification of Boxer dogs with or without ACM by increasing the number of PVCs and [hs-cTnI] in affected dogs to a greater degree than in unaffected dogs. This effect also is associated with presence or absence of the striatin mutation. Exercise should be a controlled variable when screening Boxer dogs for ACM.
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Cardiomiopatias , Doenças do Cão , Humanos , Cães , Animais , Teste de Esforço/veterinária , Estudos Prospectivos , Coração , Eletrocardiografia , Cardiomiopatias/veterináriaRESUMO
OBJECTIVE: Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM. ANIMALS: 43 client-owned cats with subclinical HCM. METHODS: Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA. RESULTS: No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups. CLINICAL RELEVANCE: Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.
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Cardiomiopatia Hipertrófica , Doenças do Gato , Hipertrofia Ventricular Esquerda , Sirolimo , Animais , Gatos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/veterinária , Cardiomiopatia Hipertrófica/patologia , Doenças do Gato/tratamento farmacológico , Doenças do Gato/patologia , Coração , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/veterinária , Hipertrofia Ventricular Esquerda/patologia , Miocárdio/patologia , Sirolimo/administração & dosagem , Preparações de Ação Retardada/administração & dosagemRESUMO
The role of taurine in the treatment of congestive heart failure (CHF) in dogs without systemic deficiency is unexplored. Taurine might have beneficial cardiac effects aside from deficit replacement. We hypothesized that oral taurine supplementation administered to dogs with naturally-occurring CHF would suppress the renin-angiotensin aldosterone system (RAAS). Oral taurine was administered to 14 dogs with stable CHF. Serum biochemical variables, blood taurine concentrations, and comprehensive analysis of RAAS variables were compared before and 2 weeks after taurine supplementation added to background furosemide and pimobendan therapy for CHF. Whole blood taurine concentrations increased after supplementation (median 408 nMol/mL, range 248-608 before and median 493 nMol/mL, range 396-690 after; P = .006). Aldosterone to angiotensin II ratio (AA2) was significantly decreased after taurine supplementation (median 1.00, range 0.03-7.05 before and median 0.65, range 0.01-3.63 after; P = .009), but no other RAAS components significantly differed between timepoints. A subset of dogs showed marked decreases in RAAS metabolites after supplementation and these dogs were more likely to have been recently hospitalized for CHF treatment than dogs that did not show marked decreases in classical RAAS metabolites. Overall, taurine only lowered AA2 in this group of dogs, however, response heterogeneity was noted, with some dogs showing RAAS suppression.
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Insuficiência Cardíaca , Sistema Renina-Angiotensina , Cães , Animais , Aldosterona/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Furosemida , Suplementos NutricionaisRESUMO
Autoantibodies to desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) in people. ARVC is a common disease in the Boxer dog. The role of anti-desmoglein-2 antibodies in Boxers with ARVC and correlation with disease status or severity is unknown. This prospective study is the first to evaluate dogs of various breeds and cardiac disease state for anti-desmoglein-2 antibodies. The sera of 46 dogs (10 ARVC Boxers, 9 healthy Boxers, 10 Doberman Pinschers with dilated cardiomyopathy, 10 dogs with myxomatous mitral valve disease, and 7 healthy non-Boxer dogs) were assessed for antibody presence and concentration via Western blotting and densitometry. Anti-desmoglein-2 antibodies were detected in all dogs. Autoantibody expression did not differ between study groups and there was no correlation with age or body weight. In dogs with cardiac disease, there was weak correlation with left ventricular dilation (r = 0.423, p = 0.020) but not left atrial size (r = 0.160, p = 0.407). In ARVC Boxers there was strong correlation with the complexity of ventricular arrhythmias (r = 0.841, p = 0.007) but not total number of ectopic beats (r = 0.383, p = 0.313). Anti-desmoglein-2 antibodies were not disease specific in the studied population of dogs. Correlation with some measures of disease severity requires further study with larger populations.
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Displasia Arritmogênica Ventricular Direita , Doenças do Cão , Animais , Cães , Autoanticorpos , Doenças do Cão/metabolismo , Átrios do Coração , Estudos Prospectivos , Desmogleína 2/imunologiaRESUMO
CASE DESCRIPTION: A 10-month-old castrated male domestic longhair cat was evaluated for increasing frequency of episodic limb rigidity. CLINICAL FINDINGS: The cat presented for falling over and lying recumbent with its limbs in extension for several seconds when startled or excited. Upon examination, the cat had hypertrophied musculature, episodes of facial spasm, and a short-strided, stiff gait. DIAGNOSTICS: Electromyography (EMG) identified spontaneous discharges that waxed and waned in amplitude and frequency, consistent with myotonic discharges. A high impact 8-base pair (bp) deletion across the end of exon 3 and intron 3 of the chloride voltage-gated channel 1 (CLCN1) gene was identified using whole genome sequencing. TREATMENT AND OUTCOME: Phenytoin treatment was initiated at 3 mg/kg po q24 h and resulted in long-term improvement. CLINICAL RELEVANCE: This novel mutation within the CLCN1 gene is a cause of myotonia congenita in cats and we report for the first time its successful treatment.
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Doenças do Gato , Miotonia Congênita , Animais , Doenças do Gato/diagnóstico , Doenças do Gato/tratamento farmacológico , Doenças do Gato/genética , Gatos , Canais de Cloreto/genética , Eletromiografia/veterinária , Éxons , Masculino , Mutação , Miotonia Congênita/diagnóstico , Miotonia Congênita/tratamento farmacológico , Miotonia Congênita/genética , Miotonia Congênita/veterináriaRESUMO
OBJECTIVE: To characterize features of myxomatous mitral valve disease (MMVD) in Miniature Schnauzers and Yorkshire Terriers. ANIMALS: 69 Miniature Schnauzers and 65 Yorkshire Terriers, each with MMVD. PROCEDURES: Medical record data for each dog were collected; the study period was January 2007 through December 2016. If available, radiographic data were evaluated, and a vertebral heart scale score was assigned for each dog. Statistical analysis was performed with Student t and Fisher exact tests. RESULTS: Compared with Yorkshire Terriers, the prevalence of MMVD was significantly higher in Miniature Schnauzers and affected dogs were significantly younger at the time of diagnosis. Miniature Schnauzers were significantly more likely to have mitral valve prolapse and syncope, compared with Yorkshire Terriers. Yorkshire Terriers were significantly more likely to have coughing and have had previous or current treatment with cardiac medications, compared with Miniature Schnauzers. There was no statistical difference between breeds with regard to abnormally high vertebral heart scale scores or radiographic evidence of congestive heart failure. CONCLUSIONS AND CLINICAL RELEVANCE: With regard to MMVD, features of the disease among Miniature Schnauzers and Yorkshire Terriers were similar, but there were also a few discernable differences between these 2 breeds and from historical findings for dogs with MMVD of other breeds. Clinical signs at the time of diagnosis differed between the 2 breeds, which may have reflected concurrent breed-specific conditions (sick sinus syndrome or airway disease [eg, tracheal collapse]). Future work should include prospective studies to provide additional information regarding the natural progression of MMVD in these dog breeds.
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Doenças do Cão , Doenças das Valvas Cardíacas , Prolapso da Valva Mitral , Animais , Doenças do Cão/epidemiologia , Cães , Doenças das Valvas Cardíacas/veterinária , Humanos , Valva Mitral , Prolapso da Valva Mitral/epidemiologia , Prolapso da Valva Mitral/veterinária , Estudos ProspectivosRESUMO
Hair length can be a highly variable trait within the Felis catus species, varying between and within different cat breeds. Previous research has demonstrated this variability is due to recessive mutations within the fibroblast growth factor 5 (FGF5) gene. Following a genetic screen, four longhaired Maine Coons were identified that had only one copy of a known FGF5 mutation. We performed DNA sequencing on samples from two of these Maine Coons and identified a missense mutation in FGF5 c.577G > A p.Ala193Thr. Genetic screening via restriction digest was then performed on samples from the other two Maine Coons and an additional 273 cats of various breeds. This screening found that only the two additional Maine Coons were heterozygous for the novel variant. Furthermore, the novel variant was not identified after in silico analysis of 68 whole genome cat sequences from various breeds, demonstrating that this novel mutation is most likely a breed-specific variant for the Maine Coon, contributing to the longhair phenotype in about 3% of these cats.
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Pelo Animal/anatomia & histologia , Gatos/genética , Fator 5 de Crescimento de Fibroblastos/genética , Mutação de Sentido Incorreto , Animais , Gatos/anatomia & histologia , Feminino , Fator 5 de Crescimento de Fibroblastos/química , Heterozigoto , Masculino , LinhagemRESUMO
BACKGROUND: The neurotransmitter serotonin (5-HT) affects valvular degeneration and dogs with myxomatous mitral valve disease (MMVD) exhibit alterations in 5-HT signaling. In Maltese dogs, 3 single nucleotide polymorphisms (SNPs) in the 5-HT transporter (SERT) gene are suggested to associate with MMVD. HYPOTHESIS/OBJECTIVES: Determine the association of SERT polymorphisms on MMVD severity and serum 5-HT concentration in Cavalier King Charles Spaniels (CKCS). Additionally, investigate the association between selected clinical and hematologic variables and serum 5-HT and assess the correlation between HPLC and ELISA measurements of serum 5-HT. ANIMALS: Seventy-one CKCS (42 females and 29 males; 7.8 [4.7;9.9] years (median [Q1;Q3])) in different MMVD stages. METHODS: This prospective study used TaqMan genotyping assays to assess SERT gene polymorphisms. Neurotransmitter concentrations were assessed by HPLC and ELISA. RESULTS: TaqMan analyses identified none of the selected SERT polymorphisms in any of the CKCS examined. Serum 5-HT was associated with platelet count (P < .001) but not MMVD severity, age or medical therapy and did not correlate with serum concentration of the 5-HT metabolite, 5-hydroxyindoleacetic acid. The ELISA serum 5-HT correlated with HPLC measurements (ρ = .87; P < .0001) but was lower (mean difference = -22 ng/mL; P = .02) independent of serum 5-HT concentration (P = .2). CONCLUSIONS AND CLINICAL IMPORTANCE: Selected SERT SNPs associated with MMVD in Maltese dogs were not found in CKCS and only platelet count influenced serum 5-HT concentration. These SNPs are unlikely to be associated with MMVD pathophysiology or serum 5-HT concentration in CKCS. HPLC and ELISA serum 5-HT demonstrated good correlation but ELISA systematically underestimated 5-HT.
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Doenças do Cão , Valva Mitral , Neurotransmissores/sangue , Proteínas da Membrana Plasmática de Transporte de Serotonina , Animais , Doenças do Cão/genética , Cães/genética , Feminino , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genéticaRESUMO
BACKGROUND: Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone. OBJECTIVES: To characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of puppies with severe upper respiratory involvement, and to identify an associated genetic variant. ANIMALS: Five of eight puppies in an Australian cattle dog cross-bred litter showed signs of skin fragility. Three were stillborn and one died at one month of age. The two surviving puppies were presented with blistering skin disease and severe respiratory distress. Additionally, one unaffected sibling was examined and blood was obtained for genetic testing. METHODS AND MATERIALS: Post-mortem examination, histopathological evaluation and electron microscopy were performed. Whole genome sequencing (WGS) of one affected puppy was compared to a database of 522 dogs of 55 different breeds for variant analysis. Sanger sequencing of one additional affected and one unaffected sibling confirmed the variant. RESULTS: Clinically, severe mucocutaneous ulcers occurred in frictional areas with claw sloughing. Histopathological results revealed subepidermal clefts and electron microscopy confirmed the split in the lamina lucida. Post-mortem examination documented extensive pharyngeal and laryngeal lesions with granulation tissue and fibrinous exudate obscuring the airway. Moderate tracheal hypoplasia contributed. The WGS revealed a novel missense variant in the laminin α3-chain XP_537297.2p(Asp2867Val), with an autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL RELEVANCE: A novel variant in LAMA3 caused a generalized and severe phenotype of JEB with an unique clinical presentation of upper airway obstruction.
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Doenças do Cão , Epidermólise Bolhosa Juncional , Laminina , Doenças da Unha , Animais , Austrália , Bovinos , Doenças do Cão/genética , Cães , Epidermólise Bolhosa Juncional/genética , Epidermólise Bolhosa Juncional/veterinária , Laminina/genética , Mutação de Sentido Incorreto , Doenças da Unha/genética , Doenças da Unha/veterináriaRESUMO
BACKGROUND: Superficial chronic corneal epithelial defects (SCCEDs) are spontaneous corneal defects in dogs that share many clinical and pathologic characteristics to recurrent corneal erosions (RCE) in humans. Boxer dogs are predisposed to SCCEDs, therefore a search for a genetic defect was performed to explain this susceptibility. DNA was extracted from blood collected from Boxer dogs with and without SCCEDs followed by whole genome sequencing (WGS). RNA sequencing of corneal tissue and immunostaining of corneal sections from affected SCCED Boxer dogs with a deletion in the NOG gene and affected non-Boxer dogs without the deletion were performed. RESULTS: A 30 base pair deletion at a splice site in Noggin (NOG) (Chr 9:31453999) was identified by WGS and was significantly associated (P < 0.0001) with Boxer SCCEDs compared to unaffected non-Boxer dogs. NOG, BMP4, MMP13, and NCAM1 all had significant fold reductions in expression and SHH was significantly increased in Boxers with the NOG deletion as identified by RNA-Seq. Corneal IHC from NOG deletion dogs with SCCEDs had lower NOG and significantly higher scores of BMP2. CONCLUSIONS: Many Boxer dogs with SCCED have a genetic defect in NOG. NOG is a constitutive protein in the cornea which is a potent inhibitor of BMP, which likely regulate limbal epithelial progenitor cells (LEPC). Dysregulation of LEPC may play a role in the pathogenesis of RCE.
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Proteínas Morfogenéticas Ósseas/metabolismo , Doenças do Cão/genética , Predisposição Genética para Doença , Animais , Proteínas Morfogenéticas Ósseas/genética , Doença Crônica , Doenças da Córnea/veterinária , Doenças do Cão/patologia , Cães , Epitélio Corneano/patologia , Regulação da Expressão Gênica , Sequenciamento Completo do GenomaRESUMO
Familial mitral valve prolapse in human beings has been associated with several genetic variants; however, in most cases, a known variant has not been identified. Dogs also have a naturally occurring form of familial mitral valve disease (MMVD) with similarities to the human disease. A shared genetic background and clinical phenotype of this disease in some dog breeds has indicated that the disease may share a common genetic cause. We evaluated DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared variants across and within breeds that could be associated with MMVD. No single causative genetic mutation was found from the 50 dogs with MMVD. Ten variants were identified in 37/50 dogs around and within the MED13L gene. These variants were no longer associated with MMVD when evaluated with a larger cohort including both affected and unaffected dogs. No high/moderate impact variants were identified in 10/10 miniature poodles, one was identified in 10/10 Yorkshire Terriers and 10/10 dachshunds, respectively, 14 were identified in 10/10 Miniature schnauzers, and 19 in 10/10 CKCS. Only one of these could be associated with the cardiac valve (Chr12:36801705, COL12A1; CKCS) but when evaluated in an additional 100 affected CKCS the variant was only identified in 84/100 affected dogs, perhaps indicating genetic heterogeneity in this disease. Our findings indicate that development of MMVD in the dog may be related to a combination of genetic and environmental factors that impact specific molecular pathways rather than a single shared genetic variant across or within breeds.
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Doenças do Cão/genética , Estudo de Associação Genômica Ampla , Doenças das Valvas Cardíacas/veterinária , Mutação , Animais , Cruzamento , Cães , Variação Genética , Doenças das Valvas Cardíacas/genética , Sequenciamento Completo do GenomaRESUMO
An 18-month-old intact male Schnauzer dog was evaluated for chronic, lifelong respiratory tract infections that were unresponsive to administration of a variety of antibiotics and corticosteroids. The dog developed persistent vomiting and diarrhea around 1 year of age that was minimally responsive to diet change, antibiotics, and corticosteroids. Despite supportive care, the dog was ultimately euthanized at 20 months of age due to persistent respiratory and gastrointestinal disease. Whole genome sequencing discovered a deleterious missense A/C mutation within the NAT10 gene, a gene essential for microtubule acetylation, appropriate ciliary development, and cytokinesis. Pipeline analysis of the genomes of 579 dogs from 55 breeds did not detect this mutation. Though never described in veterinary medicine, NAT10 mutation occurs in humans with ciliary aplasia, suggesting a pathophysiological mechanism for this dog and highlighting an associated mutation or possible novel genetic cause of chronic respiratory infections in dogs.
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Doenças do Cão , Infecções Respiratórias , Animais , Doenças do Cão/genética , Cães , Masculino , Mutação , Mutação de Sentido Incorreto , Infecções Respiratórias/genética , Infecções Respiratórias/veterinária , Sequenciamento Completo do Genoma/veterináriaRESUMO
BACKGROUND: Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation. RESULTS: A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001). CONCLUSION: This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.