2.1. Ghosal hematodiaphyseal dysplasia

At least four mutations in the TBXAS1 gene have been found to cause Ghosal hematodiaphyseal dysplasia. This condition is characterized by abnormally thick bones and a shortage of red blood cells (anemia) caused by scarring (fibrosis) of the bone marrow.

Each of the known mutations changes a single protein building block (amino acid) in thromboxane A synthase 1, which severely reduces the activity of the enzyme. A shortage of this enzyme's activity prevents the conversion of prostaglandin H₂ to thromboxane A₂. As a result, cells have more prostaglandin H₂ than usual. Prostaglandin H₂ is converted into several related molecules, including prostaglandin E₂, which is thought to be involved in bone remodeling and in controlling the growth of immature red blood cells. Researchers speculate that an increase in prostaglandin E₂ levels resulting from excess prostaglandin H₂ contributes to the bone abnormalities and anemia that occur in people with Ghosal hematodiaphyseal dysplasia. However, the exact mechanism by which a lack of thromboxane A synthase 1 activity leads to the particular features of this condition is still unclear.

A shortage of thromboxane A synthase 1 activity also reduces the level of thromboxane A₂ in cells. Although this molecule plays a critical role in hemostasis, people with Ghosal hematodiaphyseal dysplasia do not appear to have problems with blood clotting. Researchers suspect that other molecules involved in vasoconstriction and platelet aggregation may be able to compensate for the lack of thromboxane A₂ in these individuals.