Gene regulation in Van Buchem disease

Abstract

Van Buchem disease (VB) is a rare autosomal recessive disorder in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. It uniquely stands out as a congenital disorder likely to be caused by noncoding mutations for several reasons: (1) it maps to the same locus on human chromosome 17q12-21 as a highly similar disorder, sclerosteosis; (2) several single specific mutations have been identified in sclerosteosis patients that all predict null alleles in the determinant gene, sclerostin or SOST; (3) no coding mutations in SOST have been identified in VB patients; and (4) all VB patients carry a homozygous 52-kb noncoding deletion downstream of the SOST transcript. Here, we describe how by using comparative sequence analysis, BAC recombination, and enhancer assays, in combination with the generation of transgenic and knockout mice, it has been shown that human SOST is essential for maintaining healthy bone metabolism and that VB disease is caused by a noncoding deletion that removes a SOST-specific regulatory element, ECR5.