Localization of the Gene for Sclerosteosis to the van Buchem Disease–Gene Region on Chromosome 17q12–q21

Abstract

Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis.

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease

“…This gene harbours different loss of function mutations within SOST in two sclerosteosis families and one isolated sclerosteosis patient. 26 These findings are consistent with the identification of another loss of function mutation in SOST in sclerosteosis patients from the Afrikaner population in South Africa. 27 Although our data support the hypothesis that mutations in SOST result in sclerosteosis, we failed to find SOST mutations in the patients from the Dutch van Buchem family used to map the van Buchem disease locus, despite extensive mutation analysis of the SOST gene.…”

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease

“…This gene harbours different loss of function mutations within SOST in two sclerosteosis families and one isolated sclerosteosis patient. 26 These findings are consistent with the identification of another loss of function mutation in SOST in sclerosteosis patients from the Afrikaner population in South Africa. 27 Although our data support the hypothesis that mutations in SOST result in sclerosteosis, we failed to find SOST mutations in the patients from the Dutch van Buchem family used to map the van Buchem disease locus, despite extensive mutation analysis of the SOST gene.…”

Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing Protein

“…We confirmed this linkage to the long arm of chromosome 17 by typing individual DNAs with D17S1299 as well as other closely linked markers such as D17S951, D17S579, D17S920, D17S791, and D17S806 (table 2). These preliminary mapping results (Beighton et al 1999; see also Gardner 1999) were consistent with the localization of sclerosteosis to 17q12-q21 in two large families from Brazil and the United States (Balemans et al 1999).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…In humans, lack of sclerostin causes sclerosteosis, a generalized skeletal hyperostosis disorder that results from elevated Wnt signaling/osteoblast activity [108,135], while non-coding deletions of gene regulatory regions that control SOST expression result in similar phenotypes [83,88]. In animal models, overexpression of human SOST causes osteopenia and limb defects [136,137], while lack of Sost in knockout mice causes 3-4 times more bone mass, consistent with human phenotypes [83].…”

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease

“…This gene harbours different loss of function mutations within SOST in two sclerosteosis families and one isolated sclerosteosis patient. 26 These findings are consistent with the identification of another loss of function mutation in SOST in sclerosteosis patients from the Afrikaner population in South Africa. 27 Although our data support the hypothesis that mutations in SOST result in sclerosteosis, we failed to find SOST mutations in the patients from the Dutch van Buchem family used to map the van Buchem disease locus, despite extensive mutation analysis of the SOST gene.…”

Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing Protein

“…We confirmed this linkage to the long arm of chromosome 17 by typing individual DNAs with D17S1299 as well as other closely linked markers such as D17S951, D17S579, D17S920, D17S791, and D17S806 (table 2). These preliminary mapping results (Beighton et al 1999; see also Gardner 1999) were consistent with the localization of sclerosteosis to 17q12-q21 in two large families from Brazil and the United States (Balemans et al 1999).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…In humans, lack of sclerostin causes sclerosteosis, a generalized skeletal hyperostosis disorder that results from elevated Wnt signaling/osteoblast activity [108,135], while non-coding deletions of gene regulatory regions that control SOST expression result in similar phenotypes [83,88]. In animal models, overexpression of human SOST causes osteopenia and limb defects [136,137], while lack of Sost in knockout mice causes 3-4 times more bone mass, consistent with human phenotypes [83].…”

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease

“…This gene harbours different loss of function mutations within SOST in two sclerosteosis families and one isolated sclerosteosis patient. 26 These findings are consistent with the identification of another loss of function mutation in SOST in sclerosteosis patients from the Afrikaner population in South Africa. 27 Although our data support the hypothesis that mutations in SOST result in sclerosteosis, we failed to find SOST mutations in the patients from the Dutch van Buchem family used to map the van Buchem disease locus, despite extensive mutation analysis of the SOST gene.…”

Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing Protein

“…We confirmed this linkage to the long arm of chromosome 17 by typing individual DNAs with D17S1299 as well as other closely linked markers such as D17S951, D17S579, D17S920, D17S791, and D17S806 (table 2). These preliminary mapping results (Beighton et al 1999; see also Gardner 1999) were consistent with the localization of sclerosteosis to 17q12-q21 in two large families from Brazil and the United States (Balemans et al 1999).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…In humans, lack of sclerostin causes sclerosteosis, a generalized skeletal hyperostosis disorder that results from elevated Wnt signaling/osteoblast activity [108,135], while non-coding deletions of gene regulatory regions that control SOST expression result in similar phenotypes [83,88]. In animal models, overexpression of human SOST causes osteopenia and limb defects [136,137], while lack of Sost in knockout mice causes 3-4 times more bone mass, consistent with human phenotypes [83].…”