Lethal White Syndrome - Inheritance and Expression

Inheritance and Expression

Genetic conditions which affect more than one physical trait—in the case of Lethal White Syndrome, both pigment cells and enteric nerve cells—are termed pleiotropic. The unusual instance of pleiotropy in LWS foals suggested early on that the syndrome was related to an important section of embryonic tissue called the neural crest. As the name suggests, the stem cells of the neural crest are precursors to nerve cells. Another cell type that descends from neural crest cells are melanocytes, pigment-producing cells found in hair follicles and skin. The migration of nerve- and melanocyte-precursors from the top of the embryo to their eventual destinations is carefully controlled by regulatory genes.

Such regulatory genes include endothelin receptor type B (EDNRB). A mutation in the middle of the EDNRB gene, Ile118Lys, causes lethal white syndrome. In this mutation, a "typo" in the DNA mistakes isoleucine for lysine. The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors.

In the case of LWS, a single copy of the EDNRB mutation, the heterozygous state, produces an identifiable trait, but with a very different outcome from the homozygous state.

To produce a foal with lethal white syndrome, both parents must be heterozygotes or carriers of the mutated gene. Without genetic testing, some carriers are misidentified as having white markings due to another gene, while some are even classified as solids.

The presence of this gene in a variety of horse populations in North America suggests that the mutation occurred in early American history, perhaps in a Spanish-type horse.