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

Am J Hum Genet. 2001 Mar;68(3):577-89. doi: 10.1086/318811. Epub 2001 Feb 9.


Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals 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. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 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 carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.

Publication types

  • Case Reports

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blacks
  • Bone Diseases / genetics*
  • Bone Diseases / pathology
  • Bone Morphogenetic Proteins*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 17*
  • Consanguinity
  • Conserved Sequence
  • Cystine
  • Female
  • Genetic Markers
  • Homozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Netherlands / ethnology
  • Pedigree
  • Proteins / chemistry
  • Proteins / genetics*
  • Recombination, Genetic
  • Sclerosis
  • Senegal / ethnology
  • South Africa
  • Whites


  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Proteins
  • SOST protein, human
  • Sost protein, rat
  • Cystine

Associated data

  • GENBANK/AF326736
  • GENBANK/AF326737
  • GENBANK/AF326738
  • GENBANK/AF326739
  • GENBANK/AF326740
  • GENBANK/AF326741
  • GENBANK/AF326742
  • GENBANK/AF326743
  • GENBANK/AF326744
  • GENBANK/AF326745
  • GENBANK/AF326746
  • GENBANK/AF326747
  • GENBANK/AF326748