Overo lethal white foal syndrome: Equine model of aganglionic megacolon (Hirschsprung disease)

Mccabe, L.; Griffin, Lewis D.; Kinzer, Alexandra; Chandler, Marge; Beckwith, J. Bruce; McCabe, Edward R.B.

doi:10.1002/ajmg.1320360319

Cited by 63 publications

(32 citation statements)

References 14 publications

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“…Incomplete melanoblast colonization of the skin results in pigmentary abnormalities. The colonization processes of melanoblasts and ENS precursors are influenced by overlapping genetic pathways as evidenced by hereditary syndromes in which defects in development of both lineages appear together as localized pigment abnormalities associated with intestinal aganglionosis (10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease.

Gariepy¹,

Williams²,

Richardson³

et al. 1998

J. Clin. Invest.

164

145

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The spotting lethal rat, a naturally occurring rodent model of Hirschsprung disease, carries a deletion in the endothelin-B receptor ( EDNRB ) gene that abrogates expression of functional EDNRB receptors. Rats homozygous for this mutation ( sl ) exhibit coat color spotting and congenital intestinal aganglionosis. These deficits result from failure of the neural crest-derived epidermal melanoblasts and enteric nervous system (ENS) precursors to completely colonize the skin and intestine, respectively. We demonstrate that during normal rat development, the EDNRB mRNA expression pattern is consistent with expression by ENS precursors throughout gut colonization. We used the human dopamine-␤ -hydroxylase ( D ␤ H ) promoter to direct transgenic expression of EDNRB to colonizing ENS precursors in the sl/sl rat. The D ␤ H-EDNRB transgene compensates for deficient endogenous EDNRB in these rats and prevents the intestinal defect. The transgene has no effect on coat color spotting, indicating the critical time for EDNRB expression in enteric nervous system development begins after separation of the melanocyte lineage from the ENS lineage and their common precursor. The transgene dosage affects both the incidence and severity of the congenital intestinal defect, suggesting dosage-dependent events downstream of EDNRB activation in ENS development.

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Section: Introductionmentioning

confidence: 99%

Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease.

Gariepy¹,

Williams²,

Richardson³

et al. 1998

J. Clin. Invest.

164

145

View full text Add to dashboard Cite

show abstract

“…Precursors of epidermal melanocytes migrate dorsally from the neural crest and then through the mesenchymal layer beneath the ectoderm ventrally until they eventually enter the epidermis (4). Hereditary defects in development of myenteric ganglion cells and epidermal melanocytes often appear together as localized pigment abnormalities associated with aganglionic megacolon (5)(6)(7)(8)(9). This suggests a common mechanism involved in development of these two cell lineages.…”

mentioning

confidence: 99%

“…In humans, a missense mutation of the EDNRB gene also produces congenital aganglionic megacolon, or Hirschsprung disease, associated with pigment abnormalities (Shah-Waardenburg syndrome; MIM 277580) (20). A similar combination of phenotypes occurs in horses with overo lethal white foal syndrome (8) and rats with the spotting lethal (sl) mutation (7), suggesting the possibility that these mutations may also involve either the EDNRB or EDN3 gene.…”

mentioning

confidence: 99%

Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Gariepy

Cass

Yanagisawa³

1996

Proc. Natl. Acad. Sci. U.S.A.

199

154

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Mutations in the gene encoding the endothelin receptor type B (EDNRB) produce congenital aganglionic megacolon and pigment abnormalities in mice and humans. Here we report a naturally occurring null mutation of the EDNRB gene in spotting lethal (si) rats, which exhibit aganglionic megacolon associated with white coat color. We found a 301-bp deletion spanning the exon 1-intron 1 junction of the EDNRB gene in sl rats. A restriction fragment length polymorphism caused by this deletion perfectly cosegregates with the sl phenotype. The deletion leads to production of an aberrantly spliced EDNRB mRNA that lacks the coding sequence for the first and second putative transmembrane domains of the G-protein-coupled receptor. Radioligand binding assays revealed undetectable levels of functional EDNRB in tissues from homozygous sl/sl rats. We conclude that EDNRB plays an essential role in the normal development of two neural crest-derived cell lineages, epidermal melanocytes and enteric neurons, in three mammalian species-humans, mice, and rats. The EDNRB-deficient rat may also prove valuable in defining the postnatal physiologic role of this receptor.

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“…Beim Pferd wurden Aganglionosen als Ursache für Dilatationen vor allem im Zusammenhang mit dem "Lethal white foal syndrome" im Gastrointestinaltrakt beschrieben (Hultgren et al 1982, Vonderfecht et al 1983, Murray et al 1988, Dyke et al 1990, McCabe et al 1990, Huskamp et al 2000. Im Ösophagus wurde eine Aganglionose bei Mensch, Hund und Pferd dagegen nur selten als Ursache einer Achalasie mit folgendem Megaösophagus beschrieben.…”

Section: Diskussionunclassified

Megaoesophagus, aganglionosis and laryngeal paraplegia in a Friesian foal

Barton¹,

Seibel²,

Puff³

et al. 2009

PHK

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Megaoesophagus, aganglionosis and laryngeal paraplegia in a Friesian foalA 4 month old Friesian colt with severe dyspnoea was admitted after an oesophageal impaction to the Clinic for Horses of the University of Veterinary Medicine, Hannover. The foal suffered from severe cardiovascular depression and bronchopneumonia. It improved under intensive therapy, but it showed a remaining dyspnoea and onsetting nasal stridores. The endoscopic examination revealed a complete laryngeal collapse during inspiration and there was motordysfunction of the oesophagus. To achieve a functional improvement a laryngoplastic was performed on both sides. The foal was discharged from the clinic 14 days post surgery under lung treatment and a special feeding regime. It was admitted to the clinic again six weeks after, it had been found with an oesophageal impaction again. Despite intensive therapy the foal had to be destroyed because of a severe aspiration pneumonia. The pathohistologic examination revealed a megaoesophagus due to an aganglionosis of the oesophageus, which is frequently described in the Friesian horse. There may be an anatomical correlation to the laryngeal paraplegia.

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Overo lethal white foal syndrome: Equine model of aganglionic megacolon (Hirschsprung disease)

Cited by 63 publications

References 14 publications

Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease.

Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease.

Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Megaoesophagus, aganglionosis and laryngeal paraplegia in a Friesian foal

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