FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
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.
Get Full Text
Publication Date: 2011-07-07 PubMed ID: 21750681PubMed Central: PMC3131283DOI: 10.1371/journal.pgen.1002133Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

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.

Introduction

  • 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.

Findings

  • 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.

Significance

  • 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

APA
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. https://doi.org/10.1371/journal.pgen.1002133

Publication

PLoS genetics
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.

                References

                This article includes 32 references
                1. Scholes SF, Holliman A, May PD, Holmes MA. A syndrome of anaemia, immunodeficiency and peripheral ganglionopathy in Fell pony foals.. Vet Rec 1998 Feb 7;142(6):128-34.
                  pubmed: 9507645doi: 10.1136/vr.142.6.128google scholar: lookup
                2. Thomas GW, Bell SC, Phythian C, Taylor P, Knottenbelt DC, Carter SD. Aid to the antemortem diagnosis of Fell pony foal syndrome by the analysis of B lymphocytes.. Vet Rec 2003 May 17;152(20):618-21.
                  pubmed: 12790165doi: 10.1136/vr.152.20.618google scholar: lookup
                3. Thomas GW, Bell SC, Carter SD. Immunoglobulin and peripheral B-lymphocyte concentrations in Fell pony foal syndrome.. Equine Vet J 2005 Jan;37(1):48-52.
                  pubmed: 15651734doi: 10.2746/0425164054406847google scholar: lookup
                4. Bell SC, Savidge C, Taylor P, Knottenbelt DC, Carter SD. An immunodeficiency in Fell ponies: a preliminary study into cellular responses.. Equine Vet J 2001 Nov;33(7):687-92.
                  pubmed: 11770991doi: 10.2746/042516401776249309google scholar: lookup
                5. Dixon JB, Savage M, Wattret A, Taylor P, Ross G, Carter SD, Kelly DF, Haywood S, Phythian C, Macintyre AR, Bell SC, Knottenbelt DC, Green JR. Discriminant and multiple regression analysis of anemia and opportunistic infection in Fell pony foals.. Vet Clin Pathol 2000;29(3):84-86.
                  pubmed: 12070803doi: 10.1111/j.1939-165x.2000.tb00408.xgoogle scholar: lookup
                6. Fox-Clipsham L, Swinburne JE, Papoula-Pereira RI, Blunden AS, Malalana F, Knottenbelt DC, Carter SD. Immunodeficiency/anaemia syndrome in a Dales pony.. Vet Rec 2009 Sep 5;165(10):289-90.
                  pubmed: 19734561doi: 10.1136/vr.165.10.289google scholar: lookup
                7. Thomas GW. Immunodeficiency in Fell Ponies. PhD thesis:University of Liverpool; 2003.
                8. Shin EK, Perryman LE, Meek K. A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation.. J Immunol 1997 Apr 15;158(8):3565-9.
                  pubmed: 9103416
                9. Wiler R, Leber R, Moore BB, VanDyk LF, Perryman LE, Meek K. Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA-dependent protein kinase activity.. Proc Natl Acad Sci U S A 1995 Dec 5;92(25):11485-9.
                  pmc: PMC40426pubmed: 8524788doi: 10.1073/pnas.92.25.11485google scholar: lookup
                10. McGuire TC, Banks KL, Davis WC. Alterations of the thymus and other lymphoid tissue in young horses with combined immunodeficiency.. Am J Pathol 1976 Jul;84(1):39-54.
                  pmc: PMC2032354pubmed: 937516
                11. Perryman LE. Primary immunodeficiencies of horses.. Vet Clin North Am Equine Pract 2000 Apr;16(1):105-16, vii.
                  pubmed: 10752141doi: 10.1016/s0749-0739(17)30121-9google scholar: lookup
                12. Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J. The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport.. Science 2008 Aug 8;321(5890):810-4.
                  pmc: PMC3654663pubmed: 18599740doi: 10.1126/science.1160406google scholar: lookup
                13. Watanabe A, Choe S, Chaptal V, Rosenberg JM, Wright EM, Grabe M, Abramson J. The mechanism of sodium and substrate release from the binding pocket of vSGLT.. Nature 2010 Dec 16;468(7326):988-91.
                  pmc: PMC3736980pubmed: 21131949doi: 10.1038/nature09580google scholar: lookup
                14. Brandl CJ, Deber CM. Hypothesis about the function of membrane-buried proline residues in transport proteins.. Proc Natl Acad Sci U S A 1986 Feb;83(4):917-21.
                  pmc: PMC322981pubmed: 3456574doi: 10.1073/pnas.83.4.917google scholar: lookup
                15. Vilsen B, Andersen JP, Clarke DM, MacLennan DH. Functional consequences of proline mutations in the cytoplasmic and transmembrane sectors of the Ca2(+)-ATPase of sarcoplasmic reticulum.. J Biol Chem 1989 Dec 15;264(35):21024-30.
                  pubmed: 2531743
                16. Häussinger D. The role of cellular hydration in the regulation of cell function.. Biochem J 1996 Feb 1;313 ( Pt 3)(Pt 3):697-710.
                  pmc: PMC1216967pubmed: 8611144doi: 10.1042/bj3130697google scholar: lookup
                17. Kino T, Takatori H, Manoli I, Wang Y, Tiulpakov A, Blackman MR, Su YA, Chrousos GP, DeCherney AH, Segars JH. Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5.. Sci Signal 2009 Feb 10;2(57):ra5.
                  pmc: PMC2856329pubmed: 19211510doi: 10.1126/scisignal.2000081google scholar: lookup
                18. Go WY, Liu X, Roti MA, Liu F, Ho SN. NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment.. Proc Natl Acad Sci U S A 2004 Jul 20;101(29):10673-8.
                  pmc: PMC489993pubmed: 15247420doi: 10.1073/pnas.0403139101google scholar: lookup
                19. Kino T, Segars JH, Chrousos GP. The Guanine Nucleotide Exchange Factor Brx: A Link between Osmotic Stress, Inflammation and Organ Physiology and Pathophysiology.. Expert Rev Endocrinol Metab 2010 Jul 1;5(4):603-614.
                  pmc: PMC2964845pubmed: 21037977doi: 10.1586/eem.10.3google scholar: lookup
                20. Burg MB, Ferraris JD, Dmitrieva NI. Cellular response to hyperosmotic stresses.. Physiol Rev 2007 Oct;87(4):1441-74.
                  pubmed: 17928589doi: 10.1152/physrev.00056.2006google scholar: lookup
                21. Trama J, Go WY, Ho SN. The osmoprotective function of the NFAT5 transcription factor in T cell development and activation.. J Immunol 2002 Nov 15;169(10):5477-88.
                  pubmed: 12421923doi: 10.4049/jimmunol.169.10.5477google scholar: lookup
                22. Morancho B, Minguillón J, Molkentin JD, López-Rodríguez C, Aramburu J. Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice.. BMC Mol Biol 2008 Jan 25;9:13.
                  pmc: PMC2262899pubmed: 18221508doi: 10.1186/1471-2199-9-13google scholar: lookup
                23. Richards AJ, Kelly DF, Knottenbelt DC, Cheeseman MT, Dixon JB. Anaemia, diarrhoea and opportunistic infections in Fell ponies.. Equine Vet J 2000 Sep;32(5):386-91.
                  pubmed: 11037259doi: 10.2746/042516400777591174google scholar: lookup
                24. Berry GT, Wang ZJ, Dreha SF, Finucane BM, Zimmerman RA. In vivo brain myo-inositol levels in children with Down syndrome.. J Pediatr 1999 Jul;135(1):94-7.
                  pubmed: 10393611doi: 10.1016/s0022-3476(99)70334-3google scholar: lookup
                25. Berry GT, Wu S, B첯usca R, Ren J, Gonzales LW, Ballard PL, Golden JA, Stevens MJ, Greer JJ. Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea.. J Biol Chem 2003 May 16;278(20):18297-302.
                  pubmed: 12582158doi: 10.1074/jbc.m213176200google scholar: lookup
                26. Chau JF, Lee MK, Law JW, Chung SK, Chung SS. Sodium/myo-inositol cotransporter-1 is essential for the development and function of the peripheral nerves.. FASEB J 2005 Nov;19(13):1887-9.
                  pubmed: 16174787doi: 10.1096/fj.05-4192fjegoogle scholar: lookup
                27. Schuelke M. An economic method for the fluorescent labeling of PCR fragments.. Nat Biotechnol 2000 Feb;18(2):233-4.
                  pubmed: 10657137doi: 10.1038/72708google scholar: lookup
                28. Silberstein M, Tzemach A, Dovgolevsky N, Fishelson M, Schuster A, Geiger D. Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers.. Am J Hum Genet 2006 Jun;78(6):922-35.
                  pmc: PMC1474109pubmed: 16685644doi: 10.1086/504158google scholar: lookup
                29. Excoffier L, Laval G, Schneider S. Arlequin (version 3.0): an integrated software package for population genetics data analysis.. Evol Bioinform Online 2007 Feb 23;1:47-50.
                  pmc: PMC2658868pubmed: 19325852
                30. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses.. Am J Hum Genet 2007 Sep;81(3):559-75.
                  pmc: PMC1950838pubmed: 17701901doi: 10.1086/519795google scholar: lookup
                31. Staden R, Beal KF, Bonfield JK. The Staden package, 1998.. Methods Mol Biol 2000;132:115-30.
                  pubmed: 10547834doi: 10.1385/1-59259-192-2:115google scholar: lookup
                32. Carver TJ, Rutherford KM, Berriman M, Rajandream MA, Barrell BG, Parkhill J. ACT: the Artemis Comparison Tool.. Bioinformatics 2005 Aug 15;21(16):3422-3.
                  pubmed: 15976072doi: 10.1093/bioinformatics/bti553google scholar: lookup

                Citations

                This article has been cited 9 times.
                1. Polani S, Dean M, Lichter-Peled A, Hendrickson S, Tsang S, Fang X, Feng Y, Qiao W, Avni G, Kahila Bar-Gal G. Sequence Variant in the TRIM39-RPP21 Gene Readthrough is Shared Across a Cohort of Arabian Foals Diagnosed with Juvenile Idiopathic Epilepsy. J Genet Mutat Disord 2022 Jan;1(1).
                  pubmed: 35465405
                2. Finno CJ, Aleman M, Higgins RJ, Madigan JE, Bannasch DL. Risk of false positive genetic associations in complex traits with underlying population structure: a case study. Vet J 2014 Dec;202(3):543-9.
                  doi: 10.1016/j.tvjl.2014.09.013pubmed: 25278384google scholar: lookup
                3. Metzger J, Tonda R, Beltran S, Agueda L, Gut M, Distl O. Next generation sequencing gives an insight into the characteristics of highly selected breeds versus non-breed horses in the course of domestication. BMC Genomics 2014 Jul 4;15(1):562.
                  doi: 10.1186/1471-2164-15-562pubmed: 24996778google scholar: lookup
                4. Finno CJ, Bannasch DL. Applied equine genetics. Equine Vet J 2014 Sep;46(5):538-44.
                  doi: 10.1111/evj.12294pubmed: 24802051google scholar: lookup
                5. Corbin LJ, Kranis A, Blott SC, Swinburne JE, Vaudin M, Bishop SC, Woolliams JA. The utility of low-density genotyping for imputation in the Thoroughbred horse. Genet Sel Evol 2014 Feb 4;46(1):9.
                  doi: 10.1186/1297-9686-46-9pubmed: 24495673google scholar: lookup
                6. Raudsepp T, McCue ME, Das PJ, Dobson L, Vishnoi M, Fritz KL, Schaefer R, Rendahl AK, Derr JN, Love CC, Varner DD, Chowdhary BP. Genome-wide association study implicates testis-sperm specific FKBP6 as a susceptibility locus for impaired acrosome reaction in stallions. PLoS Genet 2012;8(12):e1003139.
                  doi: 10.1371/journal.pgen.1003139pubmed: 23284302google scholar: lookup
                7. Tallmadge RL, Stokol T, Gould-Earley MJ, Earley E, Secor EJ, Matychak MB, Felippe MJ. Fell Pony syndrome: characterization of developmental hematopoiesis failure and associated gene expression profiles. Clin Vaccine Immunol 2012 Jul;19(7):1054-64.
                  doi: 10.1128/CVI.00237-12pubmed: 22593239google scholar: lookup
                8. Sharif MB, Mohaseb AF, Orlando L, Saliari K, Kunst GK, Czeika S, Mashkour M, Cucchi T, Peters J, Trixl S, Mohandesan E. Late Iron Age and Roman equine breeding north of the Alps: Genetic insights and cultural implications. iScience 2025 Sep 19;28(9):113224.
                  doi: 10.1016/j.isci.2025.113224pubmed: 40837235google scholar: lookup
                9. Julia M, Felippe B. Equine common variable immunodeficiency: lessons from 100 clinical cases. Equine Vet Educ 2024 Oct;36(10):543-554.
                  doi: 10.1111/eve.13948pubmed: 39555145google scholar: lookup
                Subscribe to our newsletter
                Join 99,928 horse owners like you who receive our email updates on horse health and nutrition.