PLoS genetics2011; 7(7); e1002133; doi: 10.1371/journal.pgen.1002133

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.
Publication Date: 2011-07-07 PubMed ID: 21750681PubMed Central: PMC3131283DOI: 10.1371/journal.pgen.1002133Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't


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The research focuses on a fatal genetic condition called Foal Immunodeficiency Syndrome (FIS) threatening the survival of rare Fell and Dales pony breeds in the UK. The study successfully identifies a mutation linked to the syndrome, opening the way for strategic breeding to eradicate the disease.


  • The Fell and Dales are indigenous UK pony breeds under threat due to declining numbers, in-breeding, and inherited diseases.
  • A significant illness affecting these breeds is Foal Immunodeficiency Syndrome (FIS), a lethal Mendelian recessive disease that results in B-lymphocyte immunodeficiency and progressive anemia.
  • Approximately 10% of all Fell ponies born each year die from FIS, endangering the breed’s long-term survival.
  • FIS’s likely spread to other breeds is a considerable concern, and during this study, FIS was identified in the Dales pony, a related breed.

Research Methodology

  • The researchers used a stepwise approach, incorporating linkage and homozygosity mapping, followed by haplotype analysis, to map the mutation.
  • The genetic analysis involved 14 FIS-affected ponies, 17 known carriers, and 10 adults of unknown carrier status, which led to the identification of a region on the chromosome (ECA) 26.
  • Afterwards, a genome-wide association study pinpointed two significant SNPs on ECA26 that showed genome-wide significance after adjustment for multiple testing.


  • The researchers found a mutation in the sodium/myo-inositol cotransporter gene (SLC5A3) causing a specific protein substitution.
  • This gene plays a critical role in the regulatory response to osmotic stress, essential in many tissues like the lymphoid tissues and during early embryonic development.
  • The researchers suggest that the substitution might alter the gene’s function, leading to failure in erythropoiesis and compromise of the immune system.


  • The research is significant as it identifies a gene mutation causing FIS, a unique condition not previously linked to a mammal disease.
  • Establishing the associated gene allows for informed selective breeding to potentially eliminate FIS from equine populations, preserving these rare pony breeds.

Cite This Article

Fox-Clipsham LY, Carter SD, Goodhead I, Hall N, Knottenbelt DC, May PD, Ollier WE, Swinburne JE. (2011). Identification of a mutation associated with fatal Foal Immunodeficiency Syndrome in the Fell and Dales pony. PLoS Genet, 7(7), e1002133.


ISSN: 1553-7404
NlmUniqueID: 101239074
Country: United States
Language: English
Volume: 7
Issue: 7
Pages: e1002133

Researcher Affiliations

Fox-Clipsham, Laura Y
  • Animal Health Trust, Newmarket, UK.
Carter, Stuart D
    Goodhead, Ian
      Hall, Neil
        Knottenbelt, Derek C
          May, Paul D F
            Ollier, William E
              Swinburne, June E

                MeSH Terms

                • Animals
                • B-Lymphocytes / immunology
                • B-Lymphocytes / pathology
                • Chromosome Mapping
                • Chromosomes / immunology
                • Genetic Predisposition to Disease
                • Genome-Wide Association Study / methods
                • Haplotypes
                • Horses / genetics
                • Humans
                • Immunologic Deficiency Syndromes / genetics
                • Mutation / genetics
                • Polymorphism, Single Nucleotide
                • Sequence Homology, Amino Acid
                • Symporters / genetics
                • Symporters / immunology

                Grant Funding

                • G0100594 / Medical Research Council
                • G0600237 / Medical Research Council
                • G0900753 / Medical Research Council
                • G0901461 / Medical Research Council

                Conflict of Interest Statement

                The authors have declared that no competing interests exist.


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