OMIA 000629-9796 : Megacolon in Equus caballus

In other species: domestic cat , pig , rabbit , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 600155

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: Also known as Hirschsprung disease. A disorder in which the large intestine (caecum, colon and sometimes the rectum) undergoes a large dilation and fills with faecal mass. Associated with incomplete migration of nerve cells to the intestine during embryonic development, resulting in lack of peristalsis and hence a build-up of faecal material.

Species-specific name: Overo lethal white foal syndrome; frame overo spotting

Species-specific symbol: OLWFS

Species-specific description: As with white spotting, the Overo coat-colour pattern is characterised by pigment spreading down both sides from the dorsal midline, giving way to lack of pigment (i.e. white) primarily on the ventral surfaces. Unfortunately, homozygosity for the Overo allele results in white or nearly white foals which die within a few days of birth: the so-called lethal white foal sysndrome (LWFS). The cause of death is intestinal obstruction resulting from a lack of nerve cells in the distal portion of the large intestine (aganglionic megacolon), which is thought to be due to a fault in the proliferation and/or migration of nerve stem cells from the neural crest of the developing embryo.

Inheritance: The Overo coat colour is dominant to normal solid colour, but lethal white foal syndrome (LWFS) is recessive (i.e. the only horses to show this disorder are homozygotes for the Overo allele).

Molecular basis: Noting that mutations in the genes for endothelin 3 (EDN3) or its receptor (EDNRB) are responsible for similar disorders in humans and rodents, Santschi et al. (1998), from the University of Minnesota, sequenced cDNA from 22 affected foals, their parents, and some solid-colour normal controls, all registered with the American Paint Horse Association. There was no variation in the EDN3 gene, but a di-nucleotide substitution (TC>AG) at nucleotides 353-354 of the gene for EDNRB, resulting in an Ile118Lys amino-acid substitution, segregates perfectly with LWFS, thereby providing a molecular explanation for the disorder in American Paint horses. In quick succession, two other research groups reported similar findings: Metallinos et al. (1998), from the University of California, found the same mutation in other US horses; and Yang et al. (1998) found the same mutation causing the same disorder in Australian horses. Interestingly, both American studies found that some non-overo horses are carriers, suggesting that the mutation has incomplete penetrance.

Prevalence: Badial et al. (2018) "developed and validated a high-resolution melting (HRM) genotyping assay to detect the OLWFS causative mutation, and . . . also determined the frequency of heterozygotes among American Paint horses in Brazil. . . . The overall estimated frequency of heterozygotes was 21.6%; however, this frequency increased to 89.5% when considering only overo horses".

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EDNRB endothelin receptor type B Equus caballus 17 NC_009160.3 (50504313..50482550) EDNRB Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
American Paint Horse Miniature Horse Pinto Horse Quarter Horse Thoroughbred Megacolon EDNRB frame overo missense EquCab2 17 g.50624658 c.353-354TC>AG p. I118K 1998 9530628 Variant coordinates gleaned from or confirmed by Table S1 of Durig et al. (2017) Anim Genet 48:123-124

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2018 Badial, P.R., Teixeira, R.B.C., Delfiol, D.J.Z., da Mota, L.S.L.S., Borges, A.S. :
Validation of high-resolution melting analysis as a diagnostic tool for endothelin receptor B mutation in American Paint horses and allele frequency estimation. Mol Cell Probes :, 2018. Pubmed reference: 30096357. DOI: 10.1016/j.mcp.2018.08.002.
2010 Bellone, RR. :
Pleiotropic effects of pigmentation genes in horses. Anim Genet 41 Suppl 2:100-10, 2010. Pubmed reference: 21070283. DOI: 10.1111/j.1365-2052.2010.02116.x.
Li, B., He, XL., Zhao, YP., Wang, XJ., Manglai, D., Zhang, YR. :
[Molecular basis and applicability in equine color genetics]. Yi Chuan 32:1133-40, 2010. Pubmed reference: 21513164.
2009 Kakoi, H., Tozaki, T., Nagata, S., Gawahara, H., Kijima-Suda, I. :
Development of a method for simultaneously genotyping multiple horse coat colour loci and genetic investigation of basic colour variation in Thoroughbred and Misaki horses in Japan. J Anim Breed Genet 126:425-31, 2009. Pubmed reference: 19912416. DOI: 10.1111/j.1439-0388.2009.00841.x.
Lewin, H.A. :
Genetics. It's a bull's market. Science 324:478-9, 2009. Pubmed reference: 19390037. DOI: 10.1126/science.1173880.
Magdesian, KG., Williams, DC., Aleman, M., LeCouteur, RA., Madigan, JE. :
Evaluation of deafness in American Paint Horses by phenotype, brainstem auditory-evoked responses, and endothelin receptor B genotype. J Am Vet Med Assoc 235:1204-11, 2009. Pubmed reference: 19912043. DOI: 10.2460/javma.235.10.1204.
Mählmann, C.h., Steiger, A. :
[Assessment of hereditary defects and dispositions of the horse under animal welfare aspects]. Schweiz Arch Tierheilkd 151:153-8, 2009. Pubmed reference: 19333900. DOI: 10.1024/0036-7281.151.4.153.
Rieder, S. :
Molecular tests for coat colours in horses. J Anim Breed Genet 126:415-24, 2009. Pubmed reference: 19912415. DOI: 10.1111/j.1439-0388.2009.00832.x.
Tryon, RC., Penedo, MC., McCue, ME., Valberg, SJ., Mickelson, JR., Famula, TR., Wagner, ML., Jackson, M., Hamilton, MJ., Nooteboom, S., Bannasch, DL. :
Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses. J Am Vet Med Assoc 234:120-5, 2009. Pubmed reference: 19119976. DOI: 10.2460/javma.234.1.120.
2002 Anon. :
All-white overo cheats death Journal of Equine Veterinary Science 22:447-448, 2002.
Lightbody, T. :
Foal with Overo lethal white syndrome born to a registered quarter horse mare. Can Vet J 43:715-7, 2002. Pubmed reference: 12240532.
2001 Anon. :
Genetic cause of overo lethal white foal syndrome Journal of Equine Veterinary Science 21:381-382, 2001.
Santschi, E.M., Vrotsos, P.D., Purdy, A.K., Mickelson, J.R. :
Incidence of the endothelin receptor B mutation that causes lethal white foal syndrome in white-patterned horses American Journal of Veterinary Research 62:97-103, 2001. Pubmed reference: 11197568.
1998 Metallinos, D.L., Bowling, A.T., Rine, J. :
A missense mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome - an equine version of Hirschsprung-disease Mammalian Genome 9:426-431, 1998. Pubmed reference: 9585428.
Purdy, A.K., Santschi, E.M., Valberg, S.J., Vrotsos, P.D., Mickelson, J.R. :
Endothelin receptor B mutation associated with lethal white foal syndrome in horses [abstract] Plant & Animal Genome VI :163 only [abstract P336], 1998.
Santschi, E.M., Purdy, A.K., Valberg, S.J., Vrotsos, P.D., Kaese, H., Mickelson, J.R. :
Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses Mammalian Genome 9:306-309, 1998. Pubmed reference: 9530628.
Yang, G.C., Croaker, D., Zhang, A.L., Manglick, P., Cartmill, T., Cass, D. :
A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS) - a horse variant of Hirschsprung-disease (HSCR) Human Molecular Genetics 7:1047-1052, 1998. Pubmed reference: 9580670.
1995 Jones, W.E. :
Overo spotting in horses Journal of Equine Veterinary Science 15:48-50, 1995.
1994 Blendinger, C., Müller, G., Bostedt, H. :
[The "lethal white foal" syndrome]. Tierarztl Prax 22:252-5, 1994. Pubmed reference: 8048034.
Bowling, A.T. :
Dominant inheritance of overo spotting in paint horses Journal of Heredity 85:222-224, 1994. Pubmed reference: 8014463.
1990 Dyke, T.M., Laing, E.A., Hutchins, D.R. :
Megacolon in 2 Related Clydesdale Foals Australian Veterinary Journal 67:463-464, 1990. Pubmed reference: 2076076.
McCabe, L., Griffin, L.D., Kinzer, A., Chandler, M., Beckwith, J.B., Mccabe, E.R.B. :
Overo Lethal White Foal Syndrome - Equine Model of Aganglionic Megacolon (Hirschsprung Disease) American Journal of Medical Genetics 36:336-340, 1990. Pubmed reference: 2363434. DOI: 10.1002/ajmg.1320360319.
1988 Murray, M.J., Parker, G.A., White, N.A. :
Megacolon with myenteric hypoganglionosis in a foal. J Am Vet Med Assoc 192:917-9, 1988. Pubmed reference: 3366678.
1987 Hultgren, B.D., Appell, L.H., Wagner, P.C., Blythe, L.L., Watrous, B.J., Slizeski, M.L., Duffield, D.A., Goldie, P., Clarkson, D., Shell, D.S. :
Current research topics in equine genetics, Part 1 Equine Practice 9:38-43, 1987.
1983 Vonderfecht, S., Bowling, A.T., Cohen, M. :
Congenital intestinal megacolon in white foals Veterinary Pathology 20:65-70, 1983. Pubmed reference: 6849219.
1982 Hultgren, B.D. :
Ileocolonic aganglionosis in white progeny of overo spotted horses Journal of the American Veterinary Medicine Association 180:289-292, 1982.
1978 Schneider, J.E., Leipold, H.W. :
Recessive lethal white in foals. Journal of Equine Medicine and Surgery 2:479–482, 1978.
1977 Trommershausen-Smith, A. :
Lethal white foals in matings of overo spotted horses. Theriogenology 8:303-311, 1977.

Edit History


  • Created by Frank Nicholas on 12 Sep 2010
  • Changed by Frank Nicholas on 11 Sep 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 19 Apr 2012
  • Changed by Frank Nicholas on 17 Aug 2018