Bone dysplasia sclerosteosis results from loss of the SOST gene product, anovel cystine knot-containing protein

Sclerosteosis is an autosomal recessive sclerosing bone dysplasia character ized by progressive skeletal overgrowth. The majority of affected individua ls have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homo zygosity mapping in Afrikaner families along with analysis of historical re combinants localized sclerosteosis to an interval of similar to2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed "SOST." Affected Afrikaners c arry a nonsense mutation near the amino terminus of the encoded protein, wh ereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a prot ein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progr essive effect on bone formation observed in individuals affected with scler osteosis, along with the data presented in this study, together suggest tha t the SOST gene encodes an important new regulator of bone homeostasis.