Mammalian Genome

, Volume 9, Issue 4, pp 306–309

Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses

  • Elizabeth M. Santschi
  • Amanda K. Purdy
  • Stephanie J. Valberg
  • Paul D. Vrotsos
  • Heather Kaese
  • James R. Mickelson
Original Contributions

Abstract

Overo lethal white syndrome (OLWS) is an inherited syndrome of foals born to American Paint Horse parents of the overo coat-pattern lineage. Affected foals are totally or almost totally white and die within days from complications due to intestinal aganglionosis. Related conditions occur in humans and rodents in which mutations in the endothelin receptor B (EDNRB) gene are responsible. EDNRB is known to be involved in the developmental regulation of neural crest cells that become enteric ganglia and melanocytes. In this report we identify a polymorphism in the equine EDNRB gene closely associated with OLWS. This Ile to Lys substitution at codon 118 is located within the first transmembrane domain of this seven-transmembrane domain Gprotein-coupled receptor protein. All 22 OLWS-affected foals examined were homozygous for the Lys118 EDNRB allele, while all available parents of affected foals were heterozygous. All but one of the parents also had an overo white body-spot phenotype. Solidcolored control horses of other breeds were homozygous for the Ile 118 EDNRB allele. Molecular definition of the basis for OLWS in Paint Horses provides a genetic test for the presence of the Lys 118 EDNRB allele and adds to our understanding of the basis for coat color patterns in the horse.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amiel J, Attie T, Jan D, Pelet A, Edery P, Bidaud C, Lacombe D, Tarn P, Simeoni J, Flori E, Nihoul-Fekete C, Munnich A, Lyonnet S (1996) Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschprang disease. Hum Mol Genet 5, 355–357PubMedCrossRefGoogle Scholar
  2. Anderson DJ (1997) Cellular and molecular biology of neural crest cell lineage determination. Trends Genet 13, 276–280PubMedCrossRefGoogle Scholar
  3. Attie T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S (1995) Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 4, 2407–2409PubMedCrossRefGoogle Scholar
  4. Auricchio A, Casari G, Staiano A, Ballabio A (1996) Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a noninbred population. Hum Mol Genet 5, 351–354PubMedCrossRefGoogle Scholar
  5. Badner JA, Sieber WK, Garver KL, and Chakravarti A (1990) A genetic study of Hirschprang disease. Am J Hum Genet 46, 568–580PubMedGoogle Scholar
  6. Baynash AG, Hosoda K, Giaid A, Richardson JA, Cheung J, Emoto N, Hammer R, Yanigasawa M (1994) Interaction of endothelin-3 with endothelin B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285PubMedCrossRefGoogle Scholar
  7. Bowling AT (1994) Dominant inheritance of overo spotting in paint horses. J Hered 85, 222–224PubMedGoogle Scholar
  8. Bowling AT (1996) In Horse Genetics, (Wallingford, UK: CAB International)Google Scholar
  9. Ceccherini I, Zhang A, Matera I, Yang G, Devoto M, Romeo G, Cass D (1995) Interstitial deletion of the endothelin-B receptor gene in the spotting lethal (sl) rat. Hum Mol Genet 4, 2089–2096PubMedCrossRefGoogle Scholar
  10. Chakravarti A (1996) Endothelin receptor mediated signaling in Hirschsprung disease. Hum Mol Genet 5, 303–307PubMedGoogle Scholar
  11. Chromzynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanididium thiocyanate-phenol-chloroform extraction. Anal Biochem 162, 156–159Google Scholar
  12. Coventry S, Yost C, Palmiter RD, Kapur RP (1994) Migration of ganglion cell precursors in the ileoceca of normal and lethal spotted embryos, a murine model for Hirschsprang disease. Lab Invest 71, 82–93PubMedGoogle Scholar
  13. Edery P, Attie T, Amiel J, Pelet A, Eng C, Hofstra RMW, Martelli H, Bidaud C, Munnich A, Lyonnet S (1996) Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprang disease (Shah-Waardenburg syndrome). Nat Genet 12, 442–444PubMedCrossRefGoogle Scholar
  14. Elshourbagy NA, Korman DR, Wu HL, Sylvester DR, Lee JA, Nuthalaganti P, Bergsma DJ, Kumar CS, Nambi P (1993) Molecular characterization and regulation of the human endothelin receptors. J Biol Chem 268, 3873–3879PubMedGoogle Scholar
  15. Gariepy CE, Cass DT, Yanagisawa M (1996) Null mutation of endothelin-B receptor gene in spotting lethal rats causes aganglionic megacolon and white coat color. Proc Natl Acad Sci USA 93, 867–872PubMedCrossRefGoogle Scholar
  16. Goldberg EL (1984) An epidemiological study of Hirschsprung’s disease. Int J Epidemiol 13, 355–363CrossRefGoogle Scholar
  17. Hofstra RMW, Osinga J, Tan-Sindhunata G, Kamsteeg EJ, Stulp RP, Van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CHCM (1996) A homozygous mutation in the endothelin-3 gene associated with a Waardenburg type 2 and Hirschsprung phenotype. Nat Genet 12, 445–447PubMedCrossRefGoogle Scholar
  18. Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung J, Giaid A, Yanagisawa M (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79, 1267–1276PubMedCrossRefGoogle Scholar
  19. Hultgren BD (1982) Ileocolonic aganglionosis in white progeny of overo spotted horses. J Am Vet Med Assoc 180, 289–292PubMedGoogle Scholar
  20. Jackson IJ (1994) Molecular and developmental genetics of mouse coat color. Annu Rev Genet 28, 189–217PubMedCrossRefGoogle Scholar
  21. Kasafuka T, Wang Y, Puri P (1996) Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprang disease. Hum Mol Genet 5, 347–349CrossRefGoogle Scholar
  22. Marklund L, Johansson Moller M, Sandburg K, Andersson L (1996) A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chestnut coat color in horses. Mamm Genome 7, 895–899PubMedCrossRefGoogle Scholar
  23. McCabe L, Griffin LD, Kinzer A, Chandler M, Beckwith JB, McCabe RB (1990) Overo lethal white foal syndrome: equine model of aganglionic megacolon (Hirschsprung disease). Am J Med Genet 36, 336–340PubMedCrossRefGoogle Scholar
  24. Metzger IL (1978) The overo lethal white cross in spotted horses. Thesis, The University of MissouriGoogle Scholar
  25. Passarge E (1967) The genetics of Hirschsprang’s disease: evidence for heterogeneous etiology and a study of 63 families. N Engl J Med 276, 138–143PubMedGoogle Scholar
  26. Passarge E (1993) Wither polygenic inheritance: mapping Hirschsprang disease. Nat Genet 4, 325–326PubMedCrossRefGoogle Scholar
  27. Pavan WJ, Mac S, Cheng M, and Tilghman SM (1995) Quantitative trait loci that modify the severity of spotting in piebald mice. Genome Res 5, 29–41PubMedCrossRefGoogle Scholar
  28. Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanigasawa M, Chakravarti A (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprang’s disease. Cell 79, 1257–1266PubMedCrossRefGoogle Scholar
  29. Schneider JE, Leipold HW (1978) Recessive lethal white in foals. J Eq Med Surg 2, 479–482Google Scholar
  30. Vonderfecht SL, Trommershausen A, Cohen M (1983) Congenital aganglionosis in white foals. Vet Pathol 20, 65–70PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc 1998

Authors and Affiliations

  • Elizabeth M. Santschi
    • 1
  • Amanda K. Purdy
    • 2
  • Stephanie J. Valberg
    • 1
  • Paul D. Vrotsos
    • 1
  • Heather Kaese
    • 2
  • James R. Mickelson
    • 2
  1. 1.Department of Clinical and Population Sciences, College of Veterinary MedicineUniversity of MinnesotaSt. PaulUSA
  2. 2.Department of Veterinary PathoBiology, College of Veterinary MedicineUniversity of MinnesotaSt. PaulUSA

Personalised recommendations