Foal immunodeficiency syndrome : identification of the causal mutation

Abstract

Foal Immunodeficiency Syndrome (FIS), is a disease that affects both Fell and Dales Ponies. FIS results in a profound anaemia and a severe deficiency in the number of circulating Bvlymphocytes. Consequently, FIS-affected foals begin to lose condition and suffer from multiple opportunistic infections; FIS is eventually fatal. Pedigree analysis, incorporating the knowledge of FIS-affected individuals, suggested that FIS is a genetic disorder, with an autosomal recessive mode of inheritance. Further, analysis of the Fell and Dales Pony stud book revealed a common founder stallion, in the maternal and paternal lineage of all Fell and Dales FIS-affected individuals. Based on this, the primary aim of this investigation was to characterise the genetic lesion responsible for FIS, and subsequently develop a diagnostic test which could be used to identify asymptomatic carriers. Two approaches were taken in this study to definitively map the FIS locus; a micro satellite whole-genome scan, and a genome-wide association study. Linkage analysis and homozygosity mapping of the micro satellite marker data revealed a single locus which showed significant linkage to FIS. This was then further supported with the genome-wide association study, using the EquineSNP50 Beadchip, which identified the same locus with a significant disease association. After additional fine-mapping of the associated region, four plausible candidate genes were identified and subsequently investigated, although none revealed the causative mutation. Therefore, the entire FIS critical interval was sequenced using next-generation re-sequencing. This led to the identification of a non-synonymous single nucleotide polymorphism, in the single ex on of the sodium/myo-inositol cotransporter gene (SLC5A 3) , which is highly associated with the FIS phenotype. This gene plays a crucial role in the osmoregulation of tissues, a process which has been shown to be extremely important in the development of lymphoid tissues, lymphocytes, peripheral nerves and during early embryonic development. Further functional studies are now required to assess the functional consequences of this mutation. The identification of this mutation has led to the development of a diagnostic test, which is not only used to identify asymptomatic carriers of FIS, but also to definitively diagnose foals which are suspected FIS-affected. Additionally, this test has been used to perform a population screen, to assess the prevalence of the FIS mutation and investigate possible transfer into other equine breeds. This revealed that carrier prevalence is approximately 40-50% in the Fell Pony and 10-20% in the Dales Pony. Further, this confirmed that the FIS mutation had transferred into the Coloured pony population. Global transcriptional changes in FIS-affected foals were evaluated as part of a pilot study. This revealed significant disruption of multiple pathways, including those responsible for the haematological system and its development, tissue development and cell growth. Due to the severe clinical presentation of the FIS-affected foals used in this study, this data provides limited information on primary consequences of the causal variant. Rather it provides a snapshot of the transcriptional changes associated with the downstream effects of the FIS-causal variant and the multiple pathological effects associated with this.EThOS - Electronic Theses Online ServiceGBUnited Kingdo