A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease.

This study discovers a genetic mutation linked to Lethal White Foal Syndrome (LWFS), a fatal condition affecting newborn foals, similar to human Hirschsprung disease. It suggests this condition is related to horses’ white-coat spot patterns, and a test can be used for its early diagnosis in breeds prone to it.

Introduction to Lethal White Foal Syndrome

• Lethal White Foal Syndrome is a fatal ailment that affects some horse breeds exhibiting a white coat spotting pattern, specifically the “frame overo” pattern.
• Offspring of such horses are mostly or entirely white and die shortly after birth due to severe intestinal blockage.
• The condition is characterized by aganglionosis in the foals, a lack of nerve ganglia in certain sections of the intestine which leads to blockage. This resembles human Hirschsprung disease.

The Role of Endothelin-B Receptor Gene in LWFS

• The researchers hypothesized that mutations in the Endothelin B Receptor gene (EDNRB), associated with some cases of Hirschsprung disease, could be involved in LWFS.
• A cDNA for the normal horse EDNRB gene was cloned and sequenced for comparison.

Findings of the Study

• In three unrelated lethal white foals, the EDNRB gene contained a 2 base pair nucleotide change that led to a missense mutation (I118K) in the first transmembrane domain of the receptor.
• This domain of the protein was of interest because of its high conservation across different species, suggesting its importance in the gene’s function.
• Seven additional unrelated lethal white foal samples were found to carry this mutation in homozygosity (both copies of the gene have the mutation).
• No such homozygotes were found in 138 other samples analyzed, indicating the mutation only exists in lethal white foals.

Implications of the Findings

• All tested horses with the “frame overo” pattern that carried one copy of the mutated gene, defining a heterozygous coat color phenotype for this mutation.
• Horses with “tobiano” markings also included some carriers, showing that tobiano is epistatic (one gene masks the expression of another) over “frame overo.”
• Some horses were carriers without exhibiting the recognized overo coat pattern phenotype, indicating the variable penetrance (effect) of the mutation.

Testing and Breeding Implications

• A test for this mutant EDNRB allele could be used across all breeds where heterozygous animals might be unknowingly bred, such as the Paint Horse, Pinto Horse, Quarter Horse, Miniature Horse, and Thoroughbred.