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

Lethal white foal syndrome (LWFS) is a congenital anomaly of horsescharacterized by a white coat colour and aganglionosis of the bowel, whichis similar to Hirschsprung disease (HSCR). We decided to investigatepossible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS asrecent studies in mutant rodents and some patients have demonstrated EDNRBdefects. First, we identified a full-length cDNA for horse EDNRB . ThiscDNA fragment contained a 1329 bp open reading frame which encoded 443amino acid residues. The predicted amino acid sequence was 89, 91 and 85%identical to human, bovine and mouse as well as rat EDNRB respectively, butonly 55% identical to the human, bovine and rat endothelin A receptor(EDNRA). Secondly, sequence analysis, together with allele-specific PCR andthe amplification- created restriction site (ACRS) technique, revealed adinucleotide TC-- >AG mutation, which changed isoleucine to lysine inthe predicted first transmembrane domain of the EDNRB protein. This wasassociated with LWFS when homozygous and with the overo phenotype whenheterozygous.