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

Mammalian Genome volume 9, pages 306–309 (1998)Cite this article

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.

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References

  • 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, 355–357

    Article  PubMed  CAS  Google Scholar 

  • Anderson DJ (1997) Cellular and molecular biology of neural crest cell lineage determination. Trends Genet 13, 276–280

    Article  PubMed  CAS  Google Scholar 

  • 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, 2407–2409

    Article  PubMed  CAS  Google Scholar 

  • 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, 351–354

    Article  PubMed  CAS  Google Scholar 

  • Badner JA, Sieber WK, Garver KL, and Chakravarti A (1990) A genetic study of Hirschprang disease. Am J Hum Genet 46, 568–580

    PubMed  CAS  Google Scholar 

  • 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, 1277–1285

    Article  PubMed  CAS  Google Scholar 

  • Bowling AT (1994) Dominant inheritance of overo spotting in paint horses. J Hered 85, 222–224

    PubMed  CAS  Google Scholar 

  • Bowling AT (1996) In Horse Genetics, (Wallingford, UK: CAB International)

    Google Scholar 

  • 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, 2089–2096

    Article  PubMed  CAS  Google Scholar 

  • Chakravarti A (1996) Endothelin receptor mediated signaling in Hirschsprung disease. Hum Mol Genet 5, 303–307

    PubMed  CAS  Google Scholar 

  • Chromzynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanididium thiocyanate-phenol-chloroform extraction. Anal Biochem 162, 156–159

    Google Scholar 

  • 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, 82–93

    PubMed  CAS  Google Scholar 

  • 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, 442–444

    Article  PubMed  CAS  Google Scholar 

  • 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, 3873–3879

    PubMed  CAS  Google Scholar 

  • 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, 867–872

    Article  PubMed  CAS  Google Scholar 

  • Goldberg EL (1984) An epidemiological study of Hirschsprung’s disease. Int J Epidemiol 13, 355–363

    Article  Google Scholar 

  • 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, 445–447

    Article  PubMed  CAS  Google Scholar 

  • 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, 1267–1276

    Article  PubMed  CAS  Google Scholar 

  • Hultgren BD (1982) Ileocolonic aganglionosis in white progeny of overo spotted horses. J Am Vet Med Assoc 180, 289–292

    PubMed  CAS  Google Scholar 

  • Jackson IJ (1994) Molecular and developmental genetics of mouse coat color. Annu Rev Genet 28, 189–217

    Article  PubMed  CAS  Google Scholar 

  • 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, 347–349

    Article  Google Scholar 

  • 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, 895–899

    Article  PubMed  CAS  Google Scholar 

  • 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, 336–340

    Article  PubMed  CAS  Google Scholar 

  • Metzger IL (1978) The overo lethal white cross in spotted horses. Thesis, The University of Missouri

  • Passarge E (1967) The genetics of Hirschsprang’s disease: evidence for heterogeneous etiology and a study of 63 families. N Engl J Med 276, 138–143

    PubMed  CAS  Google Scholar 

  • Passarge E (1993) Wither polygenic inheritance: mapping Hirschsprang disease. Nat Genet 4, 325–326

    Article  PubMed  CAS  Google Scholar 

  • 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, 29–41

    Article  PubMed  CAS  Google Scholar 

  • 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, 1257–1266

    Article  PubMed  CAS  Google Scholar 

  • Schneider JE, Leipold HW (1978) Recessive lethal white in foals. J Eq Med Surg 2, 479–482

    Google Scholar 

  • Vonderfecht SL, Trommershausen A, Cohen M (1983) Congenital aganglionosis in white foals. Vet Pathol 20, 65–70

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical and Population Sciences, College of Veterinary Medicine, University of Minnesota, 55108, St. Paul, Minnesota, USA

    Elizabeth M. Santschi, Stephanie J. Valberg & Paul D. Vrotsos

  2. Department of Veterinary PathoBiology, College of Veterinary Medicine, University of Minnesota, 295 An. Sci./Vet. Med., 1988 Fitch Ave., 55108, St. Paul, Minnesota, USA

    Amanda K. Purdy, Heather Kaese & James R. Mickelson

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  1. Elizabeth M. Santschi
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  2. Amanda K. Purdy
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  3. Stephanie J. Valberg
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  4. Paul D. Vrotsos
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  5. Heather Kaese
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  6. James R. Mickelson
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Santschi, E.M., Purdy, A.K., Valberg, S.J. et al. Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses. Mammalian Genome 9, 306–309 (1998). https://doi.org/10.1007/s003359900754

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  • DOI: https://doi.org/10.1007/s003359900754

Keywords

  • Coat Color
  • Control Horse
  • Minnesota Agricultural Experiment Station
  • EDNRB Gene
  • Intestinal Aganglionosis