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: 2.88). 04/1998; 9(4):306-9. DOI: 10.1007/s003359900754
Source: PubMed

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 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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    • "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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    • "In humans, variants in the EDNRB, PAX3 and MITF genes are involved in the Waardenburg syndrome, which is characterised by partial depigmentation, sensorineural deafness and skeletal dysmorphologies (Pingault et al. 2010). In horses, a mutation in the EDNRB gene causes the frame overo spotting phenotype in heterozygotes and the lethal white foal syndrome in the homozygous state (Santschi et al. 1998). Recently detected mutations in the PAX3 and MITF genes cause splashed white phenotypes in horses, which are sometimes accompanied by deafness (Hauswirth et al. 2012). "
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    ABSTRACT: Variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes are known to cause white spotting phenotypes in horses, which can range from the common white markings up to completely white horses. In this study, we investigated these candidate genes in 169 horses with white spotting phenotypes not explained by the previously described variants. We identified a novel missense variant, PAX3:p.Pro32Arg, in Appaloosa horses with a splashed white phenotype in addition to their leopard complex spotting patterns. We also found three novel variants in the KIT gene. The splice site variant c.1346+1G>A occurred in a Swiss Warmblood horse with a pronounced depigmentation phenotype. The missense variant p.Tyr441Cys was present in several part-bred Arabians with sabino-like depigmentation phenotypes. Finally, we provide evidence suggesting that the common and widely distributed KIT:p.Arg682His variant has a very subtle white-increasing effect, which is much less pronounced than the effect of the other described KIT variants. We termed the new KIT variants W18-W20 to provide a simple and unambiguous nomenclature for future genetic testing applications.
    Animal Genetics 05/2013; 44(6). DOI:10.1111/age.12057 · 2.21 Impact Factor
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