@article{rivas_tan_shaverdian_nguyen_wouters_stern_li_2024, title={A novel ITGA2B double cytosine frameshift variant (c.1986_1987insCC) leads to Glanzmann's thrombasthenia in a cat}, volume={3}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.17030}, DOI={10.1111/jvim.17030}, abstractNote={AbstractBackgroundGlanzmann's thrombasthenia (GT) is a congenital platelet disorder affecting approximately 1:1 000 000 people globally and characterized by impaired platelet aggregation and clot retraction. Autosomal recessive, loss‐of‐function, variants in ITGA2B or ITGB3 of the αIIbβ3 receptor cause the disease in humans. A cat affected by Glanzmann's and macrothrombocytopenia was presented to the UC Davis VMTH.Hypothesis/ObjectivesSevere thrombopathia in this cat has an underlying genetic etiology.AnimalsA single affected patient, 2 age‐matched clinically healthy controls, and a geriatric population (n = 20) of normal cats.MethodsPhysical examination and clinical pathology tests were performed on the patient. Flow cytometry and platelet aggregometry analyses for patient phenotyping were performed. Patient and validation cohort gDNA samples were extracted for Sanger sequencing of a previously identified ITGA2B (c.1986delC) variant. Reverse transcriptase PCR was performed on patient and healthy control PRP samples to verify ITGA2B variant consequence.ResultsA novel c.1986_1987insCC autosomal recessive variant in ITGA2B was identified. This variant was absent in a population of 194 unrelated cats spanning 44 different breeds. Complete loss of ITGA2B transcript and protein expression was verified by RT‐PCR and flow cytometry, explaining the underlying etiology of GT, and likely macrothrombocytopenia, in this cat.Conclusions and Clinical ImportanceThis study emphasizes the role of precision medicine in cardiovascular disease of cats and identified yet another variant that may be of utility for screening in the feline population. This study provides a small‐volume, standardized, successful protocol for adequate platelet RNA isolation and subsequent molecular assessment of gene expression in cats.}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Rivas, Victor N. and Tan, Avalene W. K. and Shaverdian, Meg and Nguyen, Nghi P. and Wouters, Jalena R. and Stern, Joshua A. and Li, Ronald H. L.}, year={2024}, month={Mar} }
@article{rivas_crofton_jauregui_wouters_yang_wittenburg_kaplan_hwee_murphy_morgan_et al._2024, title={Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy}, volume={14}, ISSN={["2045-2322"]}, url={http://dx.doi.org/10.1038/s41598-024-62840-3}, DOI={10.1038/s41598-024-62840-3}, abstractNote={Abstract Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Rivas, Victor N. and Crofton, Amanda E. and Jauregui, Carina E. and Wouters, Jalena R. and Yang, Betty S. and Wittenburg, Luke A. and Kaplan, Joanna L. and Hwee, Darren T. and Murphy, Anne N. and Morgan, Bradley P. and et al.}, year={2024}, month={May} }
@article{pypendop_rivas_bueno_chohan_barter_stern_2024, title={Correlation, agreement and concordance of cardiac output estimated by transthoracic ultrasound and transesophageal Doppler with pulmonary artery thermodilution in anesthetized cats}, url={https://doi.org/10.1016/j.vaa.2024.08.006}, DOI={10.1016/j.vaa.2024.08.006}, abstractNote={To characterize the correlation, agreement and concordance of cardiac output (CO) measured with transthoracic ultrasound and the correlation and concordance of aortic blood flow (ABF) minute distance (MD) measured by transesophageal Doppler with CO measured by pulmonary artery thermodilution (PATD) in cats.}, journal={Veterinary Anaesthesia and Analgesia}, author={Pypendop, Bruno H. and Rivas, Victor N. and Bueno, Melissa Couto and Chohan, Amandeep S. and Barter, Linda S. and Stern, Joshua A.}, year={2024}, month={Nov} }
@article{advancing treatments for feline hypertrophic cardiomyopathy the role of animal models and targeted_2023, url={https://publons.com/wos-op/publon/64488725/}, DOI={10.1016/J.CVSM.2023.05.011}, abstractNote={Feline HCM is the most common cardiovascular disease in cats , leading to devastating outcomes, including congestive heart failure (CHF), arterial thromboembolism (ATE), and sudden death. Evidence demonstrating long-term survival benefit with currently available therapies is lacking. Therefore, it is imperative to explore intricate genetic and molecular pathways that drive HCM pathophysiology to inspire the development of novel therapeutics. Several clinical trials exploring new drug therapies are currently underway, including those investigating small molecule inhibitors and rapamycin. This article outlines the key work performed using cellular and animal models that has led to and continues to guide the development of new innovative therapeutic strategies.}, journal={Veterinary Clinics of North America - Small Animal Practice}, year={2023} }
@article{kaplan_rivas_walker_grubb_farrell_fitzgerald_kennedy_pjauregui_crofton_pmclaughlin_et al._2023, title={Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic results of the RAPACAT trial}, volume={261}, ISSN={["1943-569X"]}, url={https://publons.com/wos-op/publon/65523912/}, DOI={10.2460/JAVMA.23.04.0187}, abstractNote={Abstract
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.
}, number={11}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Kaplan, Joanna L. and Rivas, Victor N. and Walker, Ashley L. and Grubb, Louise and Farrell, Aisling and Fitzgerald, Stuart and Kennedy, Susan and Pjauregui, Carina E. and Crofton, Amanda E. and Pmclaughlin, Chris and et al.}, year={2023}, month={Nov}, pages={1628–1637} }
@article{sharpe_oldach_rivas_kaplan_walker_kovacs_hwee_cremin_morgan_malik_et al._2023, title={Effects of Aficamten on cardiac contractility in a feline translational model of hypertrophic cardiomyopathy}, volume={13}, url={https://publons.com/wos-op/publon/54596599/}, DOI={10.1038/S41598-022-26630-Z}, abstractNote={AbstractHypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats and lacks efficacious pharmacologic interventions in the preclinical phase of disease. LV outflow tract obstruction (LVOTO) is commonly observed in HCM-affected patients and is a primary driver of heart failure symptoms and reduced quality of life. Novel small-molecule cardiac myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over study was performed to evaluate pharmacodynamic effects of two doses (0.3 and 1 mg/kg) of a next-in-class cardiac myosin inhibitor,aficamten(CK-3773274, CK-274), on cardiac function in cats with the A31PMYBPC3mutation and oHCM. Dose-dependent reductions in LV systolic function, LVOT pressure gradient, and isovolumetric relaxation times compared to baseline were observed. Promising beneficial effects of reduced systolic function warrant further studies of this next-in-class therapeutic to evaluate the benefit of long-term administration in this patient population.}, number={1}, journal={Scientific Reports}, author={Sharpe, Ashley N and Oldach, Maureen S and Rivas, Victor N and Kaplan, Joanna L and Walker, Ashley L and Kovacs, Samantha L and Hwee, Darren T and Cremin, Peadar and Morgan, Bradley P and Malik, Fady I and et al.}, year={2023}, pages={32} }
@article{stern_rivas_kaplan_ueda_oldach_ontiveros_kooiker_dijk_harris_2023, title={Hypertrophic cardiomyopathy in purpose-bred cats with the A31P mutation in cardiac myosin binding protein-C}, volume={13}, ISSN={["2045-2322"]}, url={https://publons.com/wos-op/publon/63367066/}, DOI={10.1038/s41598-023-36932-5}, abstractNote={AbstractWe sought to establish a large animal model of inherited hypertrophic cardiomyopathy (HCM) with sufficient disease severity and early penetrance for identification of novel therapeutic strategies. HCM is the most common inherited cardiac disorder affecting 1 in 250–500 people, yet few therapies for its treatment or prevention are available. A research colony of purpose-bred cats carrying the A31P mutation in MYBPC3 was founded using sperm from a single heterozygous male cat. Cardiac function in four generations was assessed by periodic echocardiography and measurement of blood biomarkers. Results showed that HCM penetrance was age-dependent, and that penetrance occurred earlier and was more severe in successive generations, especially in homozygotes. Homozygosity was also associated with progression from preclinical to clinical disease. A31P homozygous cats represent a heritable model of HCM with early disease penetrance and a severe phenotype necessary for interventional studies aimed at altering disease progression. The occurrence of a more severe phenotype in later generations of cats, and the occasional occurrence of HCM in wildtype cats suggests the presence of at least one gene modifier or a second causal variant in this research colony that exacerbates the HCM phenotype when inherited in combination with the A31P mutation.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Stern, Joshua A. and Rivas, Victor N. and Kaplan, Joanna L. and Ueda, Yu and Oldach, Maureen S. and Ontiveros, Eric S. and Kooiker, Kristina B. and Dijk, Sabine J. and Harris, Samantha P.}, year={2023}, month={Jun} }
@article{rivas_kaplan_kennedy_fitzgerald_crofton_farrell_grubb_jauregui_grigorean_choi_et al._2023, title={Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study}, volume={13}, ISSN={["2076-2615"]}, url={https://doi.org/10.3390/ani13203184}, DOI={10.3390/ani13203184}, abstractNote={Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.}, number={20}, journal={ANIMALS}, author={Rivas, Victor N. and Kaplan, Joanna L. and Kennedy, Susan A. and Fitzgerald, Stuart and Crofton, Amanda E. and Farrell, Aisling and Grubb, Louise and Jauregui, Carina E. and Grigorean, Gabriela and Choi, Eunju and et al.}, year={2023}, month={Oct} }
@article{rivas_ueda_stern_2023, title={Sex-specific differences and predictors of echocardiographic measures of diastolic dysfunction in rhesus macaques (Macaca mulatta)}, volume={7}, ISSN={["1600-0684"]}, url={https://doi.org/10.1111/jmp.12662}, DOI={10.1111/jmp.12662}, abstractNote={AbstractBackgroundDiastolic dysfunction in humans is an age‐related process with an overrepresentation in women. In rhesus macaques (Macaca mulatta), the incidence and predictors of diastolic dysfunction have yet to be reported.MethodsData from routine echocardiographic evaluations on clinically healthy rhesus macaques was obtained and used for univariate, bivariate, hypothesis testing, and linear regression statistical analyses interrogating differences and predictors of diastolic function.ResultsRhesus macaques fully recapitulate previously reported human hemodynamic studies. Female monkeys display impaired diastology and are at an increased risk for developing diastolic dysfunction. Age, sex, and proxies of exercise activity are confirmed predictors for measures of diastolic dysfunction, regardless of specific pathogen‐free status.ConclusionsRhesus macaques share common sex‐ and age‐related echocardiographic findings as humans, therefore, serve as a valuable translational nonhuman primate model for future studies of diastolic dysfunction. These findings confirm the importance of sex‐ and age‐matching within future rhesus macaque cardiovascular research.}, journal={JOURNAL OF MEDICAL PRIMATOLOGY}, author={Rivas, Victor N. and Ueda, Yu and Stern, Joshua A.}, year={2023}, month={Jul} }
@article{lo_li_georges_nguyen_chen_stuhlmann_oldach_rivas_fousse_harris_et al._2023, title={Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet‐dependent thrombin generation in cats}, volume={37}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/jvim.16727}, DOI={10.1111/jvim.16727}, abstractNote={AbstractBackgroundDual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban sometimes is prescribed to cats with hypertrophic cardiomyopathy at risk of thromboembolism. To date, no studies have evaluated their combined effects on platelet function.Objectives/HypothesisEvaluate the safety of DAT in healthy cats and compare, ex vivo, platelet‐dependent thrombin generation and agonist‐induced platelet activation and aggregation in cats treated with clopidogrel, rivaroxaban, or DAT. We hypothesized that DAT would safely modulate agonist‐induced platelet activation and aggregation more effectively than single agent treatment.AnimalsNine apparently healthy 1‐year‐old cats selected from a research colony.MethodsUnblinded, nonrandomized ex vivo cross‐over study. All cats received 7 days of rivaroxaban (0.6 ± 0.1 mg/kg PO), clopidogrel (4.7 ± 0.8 mg/kg PO), or DAT with defined washout periods between treatments. Before and after each treatment, adenosine diphosphate (ADP)‐ and thrombin‐induced platelet P‐selectin expression was evaluated using flow cytometry to assess platelet activation. Platelet‐dependent thrombin generation was measured by fluorescence assay. Platelet aggregation was assessed using whole blood impedance platelet aggregometry.ResultsNo cats exhibited adverse effects. Of the 3 treatments, only DAT significantly decreased the number of activated platelets (P = .002), modulated platelet activation in response to thrombin (P = .01), dampened thrombin generation potential (P = .01), and delayed maximum reaction velocity (P = .004) in thrombin generation. Like clopidogrel, DAT inhibited ADP‐mediated platelet aggregation. However, rivaroxaban alone resulted in increased aggregation and activation in response to ADP.Conclusion and Clinical ImportanceTreatment combining clopidogrel and rivaroxaban (DAT) safely decreases platelet activation, platelet response to agonists, and thrombin generation in feline platelets more effectively than monotherapy with either clopidogrel or rivaroxaban.}, number={4}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Lo, Sara T. and Li, Ronald H. L. and Georges, Catherine J. and Nguyen, Nghi and Chen, Cheyenne K. and Stuhlmann, Claire and Oldach, Maureen Sigmund and Rivas, Victor Noel and Fousse, Samantha and Harris, Samantha P. and et al.}, year={2023}, month={May}, pages={1390–1400} }
@article{rivas_stern_ueda_2023, title={The Role of Personalized Medicine in Companion Animal Cardiology}, volume={53}, ISSN={["1878-1306"]}, url={https://publons.com/wos-op/publon/65523949/}, DOI={10.1016/J.CVSM.2023.05.016}, abstractNote={Cardiomyopathies remain one of the most common inherited cardiac diseases in both human and veterinary patients. To date, well over 100 mutated genes are known to cause cardiomyopathies in humans with only a handful known in cats and dogs . This review highlights the need and use of personalized one-health approaches to cardiovascular case management and advancement in pharmacogenetic-based therapy in veterinary medicine . Personalized medicine holds promise in understanding the molecular basis of disease and ultimately will unlock the next generation of targeted novel pharmaceuticals and aid in the reversal of detrimental effects at a molecular level.}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Rivas, Victor N. and Stern, Joshua A. and Ueda, Yu}, year={2023}, month={Nov}, pages={1255–1276} }
@article{sharpe_oldach_kaplan_rivas_kovacs_hwee_morgan_malik_harris_stern_2023, title={Pharmacokinetics of a single dose of Aficamten (CK-274) on cardiac contractility in a A31P MYBPC3 hypertrophic cardiomyopathy cat model}, volume={46}, url={https://publons.com/wos-op/publon/52530096/}, DOI={10.1111/JVP.13103}, abstractNote={AbstractHypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK‐274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2 mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post‐dosing. High dose aficamten (2 mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated.}, number={1}, journal={Journal of Veterinary Pharmacology and Therapeutics}, author={Sharpe, Ashley N and Oldach, Maureen S and Kaplan, Joanna L and Rivas, Victor and Kovacs, Samantha L and Hwee, Darren T and Morgan, Bradley P and Malik, Fady I and Harris, Samantha P and Stern, Joshua A}, year={2023}, pages={52—61} }
@article{increased alpha-tocopherol metabolism in horses with equine neuroaxonal dystrophy_2021, url={https://publons.com/wos-op/publon/56367468/}, DOI={10.1111/JVIM.16233}, abstractNote={AbstractBackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM.Hypothesis/ObjectivesBased on the association of α‐tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α‐tocopherol, but not γ‐tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM‐affected horses.AnimalsVitamin E metabolism: Proof of concept (POC) study; eNAD/EDM‐affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM‐affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM‐affected (n = 12) and age‐ and sex‐matched control (n = 11‐12) horses.MethodsThe rates of α‐tocopherol/tocotrienol and γ‐tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC‐MS/MS). Quantitative reverse‐transcriptase PCR (qRT‐PCR) and droplet digital (dd)‐PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog.ResultsMetabolic rate of α‐tocopherol was increased in eNAD/EDM horses (POC,P < .0001; validation, P = .03), with no difference in the metabolic rate of γ‐tocopherol. Horses with eNAD/EDM had increased expression of the CYP4F2 equine orthologue (P = .02) but no differences in copy number.Conclusions and Clinical ImportanceIncreased α‐tocopherol metabolism in eNAD/EDM‐affected QHs provides novel insight into alterations in vitamin E processing in eNAD/EDM and highlights the need for high‐dose supplementation to prevent the clinical phenotype in genetically susceptible horses.}, journal={Journal of Veterinary Internal Medicine}, year={2021} }
@article{a nonsense variant in rap guanine nucleotide exchange factor 5 (rapgef5) is associated with equine familial isolated hypoparathyroidism in thoroughbred foals_2020, url={https://publons.com/wos-op/publon/38285852/}, DOI={10.1371/JOURNAL.PGEN.1009028}, abstractNote={Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9–54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.}, journal={PLOS Genetics}, year={2020} }
@article{trim39-rpp21 variants (delta 19insccc) are not associated with juvenile idiopathic epilepsy in egyptian arabian horses_2019, url={https://publons.com/wos-op/publon/26456235/}, DOI={10.3390/GENES10100816}, abstractNote={Juvenile idiopathic epilepsy (JIE) is an inherited disease characterized by recurrent seizures during the first year of life in Egyptian Arabian horses. Definitive diagnosis requires an electroencephalogram (EEG) performed by a veterinary specialist. A recent study has suggested that a 19 base-pair deletion, along with a triple-C insertion, in intron five of twelve (∆19InsCCC; chr20:29542397-29542425: GTTCAGGGGACCACATGGCTCTCTATAGA>TATCTTAAGACCC) of the Tripartite Motif-Containing 39-Ribonuclease p/mrp 21kDa Subunit (TRIM39-RPP21) gene is associated with JIE. To confirm this association, a new sample set consisting of nine EEG-phenotyped affected and nine unaffected Egyptian Arabian horses were genotyped using Sanger sequencing. There was no significant genotypic (P = 1.00) or allelic (P = 0.31) association with the ∆19InsCCC variant and JIE status. The previously reported markers in TRIM39-RPPB1 are therefore not associated with JIE in well-phenotyped samples. The ∆19InsCCC variant is a common variant that happens to be positioned in a highly polymorphic region in the Arabian breed.}, journal={Genes}, year={2019} }
@article{an innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in ttpa-null mice_2018, url={https://publons.com/wos-op/publon/20546746/}, DOI={10.1016/J.FREERADBIOMED.2018.02.037}, abstractNote={Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration.}, journal={Free Radical Biology and Medicine}, year={2018} }