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

By M. Brunkow, J. Gardner, J. Ness, B. Paeper, Brian R. Kovacevich, S. Proll, J. Skonier, L. Zhao, P. Sabo, Ying-Hui Fu and 8 more. American Journal of Human Genetics, 2001

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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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/73e3701250a7e08b399578616041d8d6c1949f3d

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Citations in the corpus

From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. (2010, background): “disorders Van Buchem’s disease and sclerosteosis (91, 92),”
Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody (2011, background): “Individuals who are homozygous for null mutations in SOST, the gene that encodes sclerostin, have sclerosteosis.((8,9)) This syndrome is characterized by progressive bone thickening that results in significant increases in bone mass and bone mineral density (BMD) throughout the skeleton.”
LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way (2004, background): “Sclerosterosis is a progressive bone dysplasia associated with loss-of-function mutations of a secreted protein referred to as SOST (Balemans et al., 2001; Brunkow et al., 2001).”
SOST is a target gene for PTH in bone. (2005, background): “Most importantly, SOST loss-of-function mutations in humans are the cause of the autosomal recessive bone dysplasias Sclerosteosis and Van Buchem disease, which are characterized by massive bone overgrowth throughout life and increased bone strength and serum markers of bone formation [21,23,30,31].”
Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling (2009, background): “Sclerostin, encoded by the Sost gene, is a secreted cysteine-knot protein among the DAN family, which includes proteins antagonize BMP and Wnt signaling.((11)) Sclerostin has emerged as a potent inhibitor of bone growth.”
Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength (2008, background): “Mutations in a previously undescribed gene, SOST, were identified by positional cloning as being responsible for causing sclerosteosis.((3,4)) Sclerostin, the pro-”