Search

BackgroundWarmblood Fragile Foal Syndrome Type 1 (WFFS) is an autosomal recessive disorder reported previously only in warmbloods and thought to be caused by a variant in the gene procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1, c.2032G>A, p.Gly678Arg). Given the presentation of this Thoroughbred case, we hypothesised that a similar genetic mechanism caused this phenotype.ObjectivesTo describe the pathological and genetic findings on a foal presenting to a veterinary practice in the UK with skin lesions similar to other Ehlers-Danlos Syndromes, including those documented for warmbloods with WFFS.Study designA single case report describing a genetic investigation.MethodsA Thoroughbred foal presenting as dystocia was euthanised for multiple skin lesions and developmental abnormalities. DNA extracted from the foal was tested for the PLOD1 variant (c.2032G>A, p.Gly678Arg) using the commercially available assay. To confirm causality and further interrogate potential novel causes of Ehlers-Danlos Syndrome, 1799 functional candidate genes, including PLOD1, were analysed using whole genome sequencing data generated from DNA extracted from the foal's muscle. These data were compared to 34 control samples from at least 11 other breeds. Variants were prioritised for further evaluation based on predicted impact on protein function.ResultsPost-mortem evaluation concluded that this foal suffered from a condition of collagen dysplasia. The foal was homozygous for the c.2032G>A PLOD1 variant. Only two other missense variants identified from whole genome sequencing data were also computationally predicted to be deleterious to protein function, (NPHP3 c.1253T>C, p.Leu418Pro, EPDR1 c.154G>C, p.Glu52Gln). Neither of these genes have been linked to similar phenotypes, or Ehlers-Danlos Syndrome in humans or other species and thus further investigation of these variants as the cause of EDS was not warranted.Main limitationsThis study is a single case report in the Thoroughbred with no additional cases from this breed yet identified to replicate this finding.ConclusionsGiven the clinical presentation similar to WFFS, homozygosity for the PLOD1 variant, and absence of another more plausible causal variant from the WGS experiment, we conclude that PLOD1 c.2032G>A is the likely cause of this foal's condition. This is the first documented evidence of fragile foal syndrome caused by the PLOD1 variant in a breed outside of warmbloods, the Thoroughbred. We therefore recommend a change in the name of this disorder to fragile foal syndrome type 1 (FFS) and utilisation of genetic testing in Thoroughbreds to avoid producing affected foals.

Background: Thoroughbred breeders aim to have foals born early in the season, but scientific evidence on the advantages for race performance is scarce and contradictory. Methods: The association between date of birth and purchase price as foal/yearling, with race performance by the end of the second and third years of life of Thoroughbreds racing in flat races in the United Kingdom (UK) and Ireland (IRE) was assessed using negative binomial and zero-inflated negative binomial models on the entire 2014-2015 UK/IRE foal crops (n = 28,282). Results: In total, 6666 and 9456 horses raced in UK/IRE flat racing by the end of their second and third years of life. Prize money and prize money per start decreased with each additional day beyond 1 January that the foal was born. Purchase price as foal and yearling was negatively associated with the number of races run, while it was positively associated with prize money and prizemoney per start by the end of the third year of life. Conclusions: Foals born early in the season had higher earnings by the end of their second and third years of life than foals born later. Differences were more marked among males than females. The most expensive horses sold as foals or yearlings ran fewer races but earned more prize money and prize money per start than less expensive horses. Results fromthis population-based analyses may informstrategies and management practices aiming to maximise horses' racing performance potential and increase financial returns. [ABSTRACT FROM AUTHOR]

Risk factors associated with equine reproductive efficiency have been identified along with those associated specifically with early pregnancy loss (EPL). In contrast, no studies have reported risk factors associated with abortion (loss between day 70 and 300 post-cover). Given the causes of abortion differ to those of EPL, likely too will the risk factors. A retrospective cohort study was carried out to identify risk factors associated with abortion in UK and Irish based Thoroughbreds, collecting data on 20 exposure variables over a five-year period. A generalized linear mixed model was utilized to evaluate the associations between exposure variables and abortion, with clustering of observations accounted for at the mare and farm level. Variables with a likelihood ratio test (LRT) p value <0.2 were entered into the model in a forward stepwise approach. Pregnancy outcome was available on 4,439 pregnancies from 2,510 mares. Having had two or more prior abortions (odds ratio (OR) 7.91, 95% confidence interval (CI) 2.86, 21.88), conceiving on the second or subsequent covered estrous cycle (OR 1.84, 95% CI 1.22, 2.78) and conceiving multiple conceptuses (OR 1.68, 95% CI 1.02, 2.76) were associated with an increased risk of abortion compared to null parous, first estrous cycle covers and singleton conceptions respectively. Increasing paternal age (OR 0.95, 95% CI 0.90, 0.99) was associated with a decreasing risk of abortion. Mare and farm variance were not significant in the final model, LRT p=0.43. These findings provide evidence-based data to inform Thoroughbred breeding management practices to help mitigate abortion risk.

The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechanisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental autoimmune encephalomyelitis (EAE), were investigated. Expression analysis showed that HPSE mRNA is induced in rat CD4+ antigen-specific T lymphocytes upon activation and correlates with the encephalitogenicity of the cells. Examination of the kinetics and cell type-specific expression of HPSE throughout the progression of active EAE in rats, indicated that HPSE was highly expressed in CD4+ T cells infiltrating the central nervous system (CNS) during clinical disease. Little or no HPSE expression was observed in CD8+ T cells, macrophages, or astrocytes during disease progression. To investigate the mechanism of inducible HPSE gene regulation in T cells, studies were extended into human primary T cells. HPSE mRNA, protein, and enzymatic activity were induced upon activation. Functional analysis of the human HPSE promoter identified an EGR1 binding motif that contained high inducible activity and was transactivated by EGR1. Furthermore, the treatment of primary T lymphocytes with an EGR1 siRNA inhibited inducible HPSE mRNA expression. These data provide evidence to suggest that inducible HPSE expression in primary T lymphocytes is regulated at the transcriptional level by EGR1 and is important in facilitating CD4+ T cell infiltration into the CNS to promote EAE., (© 2007 Society for Leukocyte Biology.)