Endothelin receptor B polymorphism associated with Lethal White Foal Syndrome in horses

Saint Mary's University of Minnesota, Minneapolis, Minnesota, United States
Mammalian Genome (Impact Factor: 3.07). 04/1998; 9(4):306-9. DOI: 10.1007/s003359900754
Source: PubMed


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 G-protein-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. Solid-colored control horses of other breeds were homozygous for the Ile118 EDNRB allele. Molecular definition of the basis for OLWS in Paint Horses provides a genetic test for the presence of the Lys118 EDNRB allele and adds to our understanding of the basis for coat color patterns in the horse.

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    • "There are a number of mutants in livestock and pets that have been maintained by heterozygote advantage adding significantly to the number of polymorphisms maintained by heterozygote advantage in populations. Here I have given details of the 12 best documented examples, seven of them in livestock and five in pets (see other potential examples in Santschi et al. 1998; Pailhoux et al. 2001; Cavanagh et al. 2007; Qin et al. 2010; Reissman and Ludwig 2013; Kadri et al. 2014). These mutants with a heterozygote advantage constitute a great diversity of mutation types (Tables 1 and 2) with some causing phenotypic and fitness effects because of small changes, either nonsynonymous substitutions in coding regions or small insertions or deletions that cause reading-frame changes. "
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    ABSTRACT: There are a number of mutants in livestock and pets that have a heterozygote advantage because of artificial selection for these mutants in heterozygotes and strong detrimental effects from natural selection in homozygotes. In livestock, these mutants include ones that influence milk yield in dairy cattle, fecundity in sheep, litter size in pigs, muscling in beef cattle, color in horses, lean meat content in pigs, and comb morphology in chickens. In pets, these mutants include ones that influence tail length in cats and hairlessness, muscling, color, or ridgeback hair in dogs. A large variety of mutants are responsible, including small or large deletions or insertions and single base-pair nonsynonymous changes. Many of the mutants cause loss of function for the genes involved, a change that results in the pleiotropic effects of a desired phenotype in heterozygotes and low fitness or an undesirable phenotype in mutant homozygotes. I examine how selection changes the frequency of these mutants and provide an approach to estimate the amount of artificial selection that is necessary to maintain these mutants at the high frequencies often observed. The amount of artificial selection ranges from low selection favoring heterozygotes for double muscling in whippet dogs to very strong selection favoring the "flash" (part white, part solid) heterozygote in boxer dogs and the rose comb in chickens. In several examples (rose comb in Wyandotte chickens and the hair ridge in Rhodesian ridgeback dogs), there is actually stronger selection for the mutant than against it, making the frequency of the mutant greater than 50%. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail:
    Journal of Heredity 12/2014; 106(2). DOI:10.1093/jhered/esu070 · 2.09 Impact Factor
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    • "For both receptors, the activating ligands have not been identified yet in zebrafish. In mammals, where Endothelin signalling promotes the development of melanocytes, mutations in Ednrb or its ligand Endothelin 3 (Edn3) lead to a reduction of melanocytes, as well as aganglionosis caused by a strong reduction in sensory gut neurons (Baynash et al., 1994; Gariepy et al., 1996; Hosoda et al., 1994; Kunieda et al., 1996; Metallinos et al., 1998; Santschi et al., 1998). Similar reductions in the number of melanocytes were observed in mice carrying a knock-out allele of the endothelin-converting enzyme 1 (Ece1). "
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    ABSTRACT: Colour patterns of adult fish are composed of several different types of pigment cells distributing in the skin during juvenile development. The zebrafish, Danio rerio, displays a striking pattern of dark stripes of melanophores interspersed with light stripes of xanthophores. A third cell type, silvery iridophores, contributes to both stripes and plays a crucial role in adult pigment pattern formation. Several mutants deficient in iridophore development display similar adult phenotypes with reduced numbers of melanophores and defects in stripe formation. This indicates a supporting role of iridophores for melanophore development and maintenance. One of these mutants, rose (rse), encodes the Endothelin receptor b1a. Here we describe a new mutant in zebrafish, karneol (kar), which has a phenotype similar to weak alleles of rse with a reduction in iridophore numbers and defects of adult pigment patterning. We show that, unlike rse, kar is not required in iridophores. The gene defective in the kar mutant codes for an endothelin-converting enzyme, Ece2, which activates endothelin ligands by proteolytic cleavage. By morpholino-mediated knockdown, we identify Endothelin 3b (Edn3b) as the ligand for endothelin receptor signalling in larval iridophores. Thus, Endothelin signalling is involved in iridophore development, proliferation and stripe morphogenesis in larvae as well as adult zebrafish. In mammals the pathway is required for melanocyte development; therefore, our results indicate a previously unrecognized close evolutionary relationship between iridophores in zebrafish and melanocytes in mammals.
    Biology Open 05/2014; 3(6). DOI:10.1242/bio.20148441 · 2.42 Impact Factor
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    • "The naturally occurring horse variant of Hirschsprung's disease is known as ileocolonic aganglionosis (ICA) or overo lethal white syndrome (OLWS) [Brashier and Geor, 1995; Metallinos et al., 1998; Lightbody, 2002; Finno et al., 2009], which is a fatal condition, and foals die within the first few days after birth due to an obstruction-induced intestinal severe colic and paralytic ileum [McCabe et al., 1990; Parry, 2005]. In both horses and humans, aganglionosis results from a congenital disorder of neural crest cell migration throughout the intestine (craniocaudal migration theory) [Okamoto and Ueda, 1967; Santschi et al., 1998; Lightbody, 2002]. "
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    ABSTRACT: Ileocolonic aganglionosis (ICA) is the congenital and hereditary absence of neurons that constitute the enteric nervous system and has been described in various species including humans - Hirschsprung's disease - and horses - overo lethal white syndrome (OLWS). Hirschsprung's disease affects circa 1 in 5,000 live births. At best, this disease means an inability to absorb nutrients from food (humans). At worse, in horses, it always means death. Despite our general understanding of the functional mechanisms underlying ICA, there is a paucity of reliable quantitative information about the structure of myenteric and submucosal neurons in healthy horses and there are no studies on horses with ICA. In light of these uncertainties, we have used design-based stereology to describe the 3-D structure - total number and true size - of myenteric and submucosal neurons in the ileum of ICA horses. Our study has shown that ICA affects all submucosal neurons and 99% of myenteric neurons. The remaining myenteric neurons (0.56%) atrophy immensely, i.e. 63.8%. We believe this study forms the basis for further research, assessing which subpopulation of myenteric neurons are affected by ileocolonic aganglionosis, and we would like to propose a new nomenclature to distinguish between a complete absence of neurons - aganglionosis - and a weaker form of the disease which we suggest naming 'hypoganglionosis'. Our results are a step forward in understanding this disease structurally. © 2013 S. Karger AG, Basel.
    Cells Tissues Organs 07/2013; 198(2). DOI:10.1159/000353218 · 2.14 Impact Factor
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