Identification of a Mutation Associated with Fatal Foal Immunodeficiency Syndrome in the Fell and Dales Pony

Abstract

The Fell and Dales are rare native UK pony breeds at risk due to falling numbers, in-breeding, and inherited disease. Specifically, the lethal Mendelian recessive disease Foal Immunodeficiency Syndrome (FIS), which manifests as B-lymphocyte immunodeficiency and progressive anemia, is a substantial threat. A significant percentage (∼10%) of the Fell ponies born each year dies from FIS, compromising the long-term survival of this breed. Moreover, the likely spread of FIS into other breeds is of major concern. Indeed, FIS was identified in the Dales pony, a related breed, during the course of this work. Using a stepwise approach comprising linkage and homozygosity mapping followed by haplotype analysis, we mapped the mutation using 14 FIS–affected, 17 obligate carriers, and 10 adults of unknown carrier status to a ∼1 Mb region (29.8 – 30.8 Mb) on chromosome (ECA) 26. A subsequent genome-wide association study identified two SNPs on ECA26 that showed genome-wide significance after Bonferroni correction for multiple testing: BIEC2-692674 at 29.804 Mb and BIEC2-693138 at 32.19 Mb. The associated region spanned 2.6 Mb from ∼29.6 Mb to 32.2 Mb on ECA26. Re-sequencing of this region identified a mutation in the sodium/myo-inositol cotransporter gene ( SLC5A3); this causes a P446L substitution in the protein. This gene plays a crucial role in the regulatory response to osmotic stress that is essential in many tissues including lymphoid tissues and during early embryonic development. We propose that the amino acid substitution we identify here alters the function of SLC5A3, leading to erythropoiesis failure and compromise of the immune system. FIS is of significant biological interest as it is unique and is caused by a gene not previously associated with a mammalian disease. Having identified the associated gene, we are now able to eradicate FIS from equine populations by informed selective breeding.

Author Summary

Foal Immunodeficiency Syndrome (FIS) is a genetic disease that affects two related British pony breeds, namely the Fell and the Dales. Foals with FIS appear to be normal at birth but within a few weeks develop evidence of infection such as diarrhoea, pneumonia, etc. The infections are resistant to treatment, and the foals die or are euthanized before three months of age. The foals also suffer from a severe progressive anemia. Being a recessive condition, the disease is difficult to control without a diagnostic DNA test to identify symptom-free carrier parents. Within the last few years the horse genome has been sequenced, and this has allowed the development of tools to identify genetic mutations in the horse at high resolution. In this article we demonstrate the use of these new tools to identify the location of the FIS mutation. The presumptive causal lesion was then identified by sequencing this region. This has enabled us to develop a test that can be used to identify carrier ponies, allowing breeders to avoid FIS in their foal crop.