A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease.

This research study explores how a specific mutation in the endothelin-B receptor gene (EDNRB) in horses is associated with a fatal genetic disorder called Lethal White Foal Syndrome (LWFS). LWFS is similar to Hirschsprung’s disease in humans, where the large intestine is not functional due to a lack of nerve cells.

Investigating EDNRB Mutations in LWFS

• The researchers started by focusing on possible mutations to the EDNRB gene. This focus was motivated by earlier studies comparing mutant rodents and some patients, both of which displayed defects in the EDNRB.
• They successfully identified a full-length cDNA for the horse EDNRB, which contained an open reading frame of 1329 base pairs (bp), encoding 443 amino acid residues.

Comparison to other Species

• The program posited that the amino acid sequence was largely identical to the EDNRB known from other species (89% to human, 91% to bovine, 85% to mouse and rat), but only 55% identical to the endothelin A receptor (EDNRA) in human, bovine, and rat.

Detection of Mutation

• Performing a sequence analysis alongside allele-specific PCR and the utilisation of the Amplification-Created Restriction Site (ACRS) technique, a dinucleotide mutation was revealed. Specifically, a TC changed to AG, which resulted in the amino acid isoleucine being replaced by lysine in the predicted first transmembrane domain of the EDNRB protein.
• Significantly, this mutation was associated with LWFS when the mutation was present on both inherited alleles (homozygous). Conversely, when the mutation was present on just one inherited allele (heterozygous), it was associated with the overo phenotype, a term that describes the color and patterning in certain horses.

In conclusion, the findings in this study provide a deeper understanding of the genetic basis of lethal white foal syndrome in horses and add to our understanding of the genetic mechanisms underlying Hirschsprung’s disease in humans.