SOST gene

At least six mutations in or near the SOST gene have been found to cause SOST-related sclerosing bone dysplasia. There are two forms of SOST-related sclerosing bone dysplasia: sclerosteosis and van Buchem disease. Sclerosteosis, the more severe type, is most common in the Afrikaner population of South Africa, while the milder van Buchem disease occurs most often in people of Dutch ancestry.

Most mutations that cause sclerosteosis result in a premature stop signal in the instructions for making sclerostin. These mutations prevent the production of any functional protein.

The most common mutation that causes van Buchem disease in people of Dutch ancestry is a deletion of 52,000 DNA building blocks (nucleotides) in a region of DNA neighboring the SOST gene. This region, called a regulatory region, normally controls the gene's activity (expression). This deletion within the regulatory region reduces the expression of the SOST gene, leading to a shortage of functional sclerostin protein.

A shortage or absence of sclerostin in bone cells disrupts the protein's inhibitory effect on bone growth, causing excessive bone formation. As a result, bones are denser and wider than usual, particularly the bones of the skull. These bone abnormalities are characteristic of SOST-related sclerosing bone dysplasia.