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Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Open accessAbstract
Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.
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“Inactivating mutations of this gene can produce the high-bone-mass disorder Van Buchem disease or sclerosteosis”
From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [73]
Experimental — accuracy not yet measuredIn the citing paper
“Mutations in genes that have highly enriched expression in osteocytes cause rare bone and mineral disorders.”
From Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease (2021) · cites this paper as [18]
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Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models
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Recent Advances in Osteoclast Biological Behavior
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“Sclerostin, which is encoded by the SOST gene, is an anti-anabolic protein that inhibits bone growth (Balemans et al., 2001;Winkler et al., 2003).”
BackgroundNMR structure of the Wnt modulator protein Sclerostin
Weidauer, S. E., Schmieder, P., Beerbaum, M., Schmitz, W., Oschkinat, H., & Mueller, T. D. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.01.062 · Cited by 81
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BackgroundTGF‐β signaling in human skeletal and patterning disorders
Serra, R. A., & Chang, C. (2003) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.10023 · Cited by 80
Hormonal and systemic regulation of sclerostin
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“humans and subsequently confirmed in murine models, inactivating mutations in SOST, the gene which encodes the sclerostin protein, are associated with significant increases in rates of bone formation and bone mass [1, 2].”
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“Loss of function mutations in the sost gene or in its regulatory elements causes two rare human genetic disorders, sclerosteosis [7, 8] and van Buchem disease [9, 10] that result in high bone mass.”
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Balemans, W., Cleiren, E., SIEBERS, U., Horst, J., & Hul, W. V. (2005) · Bone · doi:10.1016/j.bone.2005.02.019 · Cited by 79
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“, 2004), and bone overgrowth of humans with LRP4 mutations is reminiscent of bone defects caused by SOST and DKK1 mutations (Balemans et al., 2001; Morvan et al., 2006).”
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“A large number of investigators have looked for evidence of an association between ESR1 alleles and BMD, mostly focusing on two polymorphisms within intron 1, recognised by the XbaI and PvuII restriction enzymes.”
Sclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats
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“Sclerostin, encoded by the sost gene, is a potent inhibitor of bone formation.((5,25,26)) Several elegant animal studies have shown sclerostin levels are inversely proportional to bone mass((5,7)) and that production of sclerostin by osteocytes is dramatically reduced by mechanical loading in rodents.”
BackgroundCbfa1/RUNX2 Directs Specific Expression of the Sclerosteosis Gene (SOST)
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Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains
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“Mutations in SOST cause the severe bone overgrowth disorders sclerosteosis,((15,16)) van Buchem disease (VBD), and autosomal dominant craniodiaphyseal dysplasia (CDD).”
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“It is known to play an anabolic role in bone formation by osteoblasts, and perturbation of this pathway is known to be involved in other sclerosing bone dysplasias such as Van Buchem disorder, sclerosteosis, and the high-bone-mass phenotype.((9,10)) In addition to OSCS, WTX is known to be mutated in a significant perc…”
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Shahar, R., & Dean, M. N. (2013) · BoneKEy Reports · doi:10.1038/bonekey.2013.77 · Cited by 75
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Anti-Sclerostin Antibodies in Osteoporosis and Other Bone Diseases
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“humans and murine knockout models [30,31,32,33]; a related disease, van Buchem’s disease (OMIM ID 239100), is caused by a distal noncoding deletion that removes regulatory elements required for the transcriptional of the Sost gene in adult bone [32].”
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“Humanswith inherited sclerostin deficiency (sclerosteosis and van Buchem disease) show increased bone mass [1–3].”
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Maresova, K. B., Pavelká, K., & Stepan, J. J. (2012) · Calcified Tissue International · doi:10.1007/s00223-012-9684-4 · Cited by 73
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“[78] Loss of function Sost mutations cause the greatly increased bone mass of sclerosteosis and van Buchem’s disease.[79,80] Physiologically, rapid reductions in sclerostin could signal to limit the filling of remodeling spaces by osteoblasts, in ad-”
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“A similar high bone mass (HBM) phenotype has been reported among patients with mutations in the SOST gene, or in its distant regulatory elements, which are linked to the sclerosing bone disorders Sclerosteosis and van Buchem's disease [6–8].”
Molecular genetics of too much bone
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“Although at least five different inactivating mutations of the SOST gene have been identified in sclerosteosis, no mutations have been seen in van Buchem’s disease [15, 16].”
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“As a result of the hyperostosis of the skull, sclerosteosis patients have clinical symptoms, such as facial palsy, deafness and blindness due to compression of the cranial nerves (Table 5) [205–210].”
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“Loss-of-function mutations in SOST in human results in increased bone mass.((16,17)) Following in vivo mechanical loading, SOST/sclerostin is downregulated,((18)) whereas expression of sclerostin is increased in osteocytes after hindlimb unloading.”
BackgroundTNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition
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Is bone quality associated with collagen age?
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“, sclerosteosis and Van Buchem disease), which result primarily from increased bone formation, the phenotype is associated with improved bone strength and lower fracture risk [58–60].”
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“Mutations and deletions in SOST have been linked to the autosomal recessive diseases sclerosteosi”
BackgroundEhnert, S., Zhao, J., Pscherer, S., Freude, T., Dooley, S., Kolk, A., Stöckle, U., Nussler, A. K., & Hube, R. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-101 · Cited by 67
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“High bone mass has also been observed in patients with sclerosteosis [10] and Van Buchem's disease [11], two conditions associated with defective sclerostin production.”
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Sclerostin Antibody Increases Bone Volume and Enhances Implant Fixation in a Rat Model
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First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function
Piters, E., Çulha, C., Moester, M. J. C., Bezooijen, R. V., Adriaensen, D., Mueller, T. D., Weidauer, S. E., Jennes, K., de Freitas, F., Löwik, C., et al. (2010) · Human Mutation · doi:10.1002/humu.21274 · Cited by 64
Determination of Serum and Plasma Sclerostin Concentrations by Enzyme-Linked Immunoassays
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“Recessive genetic disorders resulting in loss of sclerostin cause the clinical high-bone-mass disorders sclerosteosis((21,22)) and van Buchem disease.”
BackgroundClinical and Biological Determinants of Sclerostin Plasma Concentration in Hemodialysis Patients
Delanaye, P., Krzesinski, J.-M., Warling, X., Moonen, M., Smelten, N. S., Médart, L., Bruyère, O., Reginster, J., Pottel, H., & Cavalier, E. (2014) · Nephron Clinical Practice · doi:10.1159/000366449 · Cited by 62
Osteocytes: central conductors of bone biology in normal and pathological conditions
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“…Buchem disease, two closely related bone disorders, respectively, because ofa loss of function and deletion of the SOST gene, are characterized by high bone mass (Balemans et al. 2001, 2002); on the contrary, transgenic mice with overexpression of sclerostin are osteopenic (Winkler et al. 2003).”
BackgroundMedicamentos para o tratamento da osteoporose: revisão
Khajuria, D. K., Razdan, R., & Mahapatra, D. R. (2011) · Revista Brasileira de Reumatologia · doi:10.1590/s0482-50042011000400008 · Cited by 120
van Dinther, M., Zhang, J., Weidauer, S. E., Boschert, V., Muth, E.-M., Knappik, A., de Gorter, D. J. J., van Kasteren, P. B., Frisch, C., Mueller, T. D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062295 · Cited by 61
“inactivation of its product Sclerostin [11,12].”
Yavropoulou, M. P., van Lierop, A. H., Hamdy, N. A. T., Rizzoli, R., & Papapoulos, S. E. (2012) · Bone · doi:10.1016/j.bone.2012.04.016 · Cited by 61
“Sclerostin has attracted much attention over the last few years due to its implication in the pathogenesis of two rare skeletal disorders characterized by substantial increase in bone mass, sclerosteosis and van Buchem disease [6–9].”
BackgroundKim, R. Y., Yang, H. J., Song, Y. M., Kim, I. S., & Hwang, S. J. (2015) · Tissue Engineering Part A · doi:10.1089/ten.tea.2014.0585 · Cited by 63
Séror, R., Boudaoud, S., Pavy, S., Nocturne, G., Schaeverbeke, T., Saraux, A., Chanson, P., Gottenberg, J., Devauchelle‐Pensec, V., Tobón, G. J., et al. (2016) · Scientific Reports · doi:10.1038/srep18421 · Cited by 62
Pharmacological and biological therapeutic strategies for osteogenesis imperfecta
Marom, R., Lee, Y., Grafe, I., & Lee, B. (2016) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31532 · Cited by 59
“Pathogenic loss-of-function variants in the SOST gene cause sclerosteosis, a rare disorder characterized by high bone mass [Balemans et al., 2001; Brunkow et al., 2001].”
An integrated multi-omics analysis reveals osteokines involved in global regulation
Liang, W., Wei, T., Hu, L., Chen, M., Tong, L., Zhou, W., Duan, X., Zhao, X., Zhou, W., Jiang, Q., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.006 · Cited by 67
Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges
MacNabb, C., Patton, D., & Hayes, J. S. (2016) · Journal of Osteoporosis · doi:10.1155/2016/6217286 · Cited by 61
Wang, T., Yu, X., & He, C. (2018) · Current Drug Targets · doi:10.2174/1389450119666180405094046 · Cited by 61
Cardiovascular Safety and Sclerostin Inhibition
Langdahl, B. L., Hofbauer, L. C., & Forfar, J. C. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab193 · Cited by 64
McDonald, M., Morse, A., Mikulec, K., Peacock, L., Yu, N., Baldock, P., Birke, O., Liu, M., Ke, H., & Little, D. (2012) · Journal of Orthopaedic Research · doi:10.1002/jor.22109 · Cited by 59
“Sclerostin is a negative regulator of bone formation which was discovered through the detection of a mutation in the SOST gene in patients diagnosed with the high bone mass disease, sclerosteosis.(1) Parallel to the human disease, mice with a targeted deletion of SOST demonstrate an extremely high bone mass phenotype,…”
BackgroundTGF-β regulates sclerostin expression via the ECR5 enhancer
Loots, G. G., Keller, H., Leupin, O., Murugesh, D. K., Collette, N. M., & Genetos, D. C. (2011) · Bone · doi:10.1016/j.bone.2011.11.016 · Cited by 59
“As activating mutations in LRP4-6 promote high bone mass (HBM) phenotypes [1, 2, 7, 8], complementary phenotypes emerge from deletion of Lrp4/5/6 antagonists [9–15]: deletion of sFRPs increases trabecular bone [15] and bone mineral density [14], and deletion of DKK isoforms or SOST increases markers of bone formation…”
BackgroundLeukemia inhibitory factor: A paracrine mediator of bone metabolism
Sims, N. A., & Johnson, R. W. (2012) · Growth Factors · doi:10.3109/08977194.2012.656760 · Cited by 66
“This factor is expressed strongly by osteocytes and is critical for normal bone formation; lack of sclerostin in humans and mice leads to a condition of high bone mass, termed sclerosteosis (Balemans et al. 2001; Loots et al. 2005), and antisclerostin agents are showing promise as therapies to stimulate bone formation…”
BackgroundNovel advances in the treatment of osteoporosis
Chan, C. K. Y., Mason, A., Cooper, C. C., & Dennison, E. M. (2016) · British Medical Bulletin · doi:10.1093/bmb/ldw033 · Cited by 59
“Indeed patients with a genetic deficiency of sclerostin (van Buchem disease) have high bone mass and correspondingly increased bone strength that is resistant to fractures.(32) These patients tend to lead a normal life with nerve entrapment being the only problem of the high skeletal BMD.”
BackgroundOsteocytic FGF23 and Its Kidney Function
Agoro, R., Ni, P., Noonan, M. L., & White, K. E. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00592 · Cited by 59
Mundy, G. R., Oyajobi, B. O., Gutierrez, G. E., Sterling, J. A. R., Padalecki, S. S., Elefteriou, F., & Zhao, M. (2008) · Elsevier eBooks · doi:10.1016/b978-012370544-0.50020-3 · Cited by 59
Sclerostin Deficiency Is Linked to Altered Bone Composition
Hassler, N., Roschger, A., Gamsjaeger, S., Krämer, I., Lueger, S., van Lierop, A. H., Roschger, P., Klaus Klaushofer, A., Paschalis, E. P., Kneissel, M., et al. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2259 · Cited by 58
“Once acquired, the Raman spectra were baseline corrected (rubber band, 5 iterations), and the following Raman parameters were calculated as published elsewhere: (1) the relative proteoglycan content was expressed as the proteoglycan/organic matrix ratio (the ratio of the integrated areas of the proteoglycan/CH3 [1365…”
MethodOsteocytes and Skeletal Pathophysiology
Delgado‐Calle, J., & Bellido, T. (2015) · Current Molecular Biology Reports · doi:10.1007/s40610-015-0026-y · Cited by 62
“Functional mutations of the SOST gene cause abnormal skeletal phenotypes in humans, characterized by high bone mineral density (104;105).”
BackgroundWalker, E. C., Poulton, I. J., McGregor, N. E., Ho, P. W. M., Allan, E. H., Quach, J., Martin, T. J., & Sims, N. A. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1506 · Cited by 59
“Sclerostin is critical for normal bone mass: mutations in sclerostin that lead to its inactivation result in sclerosteosis, a syndrome of greatly increased bone mass.((23)) Downregulation of sclerostin also plays a role in the enhanced bone formation that occurs in response to mechanical stimulation,((24)) and consist…”
BackgroundTian, X., Setterberg, R. B., Li, X., Pászty, C., Ke, H. Z., & Jee, W. S. S. (2010) · Bone · doi:10.1016/j.bone.2010.05.032 · Cited by 56
“Genetics and gene expression analysis have demonstrated that the osteocyte-secreted protein sclerostin, encoded by the SOST gene, is a potent inhibitor of bone formation [6–9].”
BackgroundAnabolic Agents and Bone Quality
Sibai, T. A., Morgan, E. F., & Einhorn, T. A. (2010) · Clinical Orthopaedics and Related Research · doi:10.1007/s11999-010-1722-9 · Cited by 58
“SOST cause skeletal dysplasias characterized by increased bone mass, sclerosteosis, and van Buchem’s syndrome [8].”
Osteoporosis: A Silent Disease with Complex Genetic Contribution
Golchin, M. M., Heidari, L., Ghaderian, S. M. H., & Akhavan‐Niaki, H. (2016) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2015.12.001 · Cited by 58
“The MEF2C also plays a key role in regulating SOST gene expression (Leupin et al., 2007).”
BackgroundInfluentialSingle-Cell RNA Sequencing of Calvarial and Long-Bone Endocortical Cells
Ayturk, U. M., Scollan, J. P., Aytürk, D. G., Suh, E. S., Vesprey, A., Jacobsen, C. M., Pajevic, P. D., & Warman, M. L. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4052 · Cited by 59
“In humans, SOST deficiency causes two high bone mass disorders sclerosteosis and Van Buchem disease,((19,20)) which are recapitulated by Sost-null mice.”
BackgroundBone mineral density and mortality in end-stage renal disease patients
Iseri, K., Dai, L., Chen, Z., Qureshi, A. R., Brismar, T. B., Stenvinkel, P., & Lindholm, B. (2020) · Clinical Kidney Journal · doi:10.1093/ckj/sfaa089 · Cited by 57
“While mutations in SOST may increase bone mass [114, 115], overexpression of Dickkopf-related protein 1 (DKK1), another inhibitor of Wnt signalling, causes osteopaenia, whereas DKK1 insufficiency increases bone formation [116].”
BackgroundSclerostin Antibody Treatment Improves Implant Fixation in a Model of Severe Osteoporosis
Virdi, A. S., Irish, J., Sena, K., Liu, M., Ke, H. Z., McNulty, M. A., & Sumner, D. R. (2015) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.n.00654 · Cited by 60
Differential sclerostin and parathyroid hormone response to exercise in boys and men
Falk, B., Haddad, F., Klentrou, P., Ward, W. E., Kish, K., Mezil, Y., & Radom‐Aizik, S. (2015) · Osteoporosis International · doi:10.1007/s00198-015-3310-z · Cited by 56
“Sclerosteosis and van Buchem disease are both characterized by low sclerostin levels, which allow for greater bone formation, resulting in high bone mineral density [6, 7].”
The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing
Heilmann, A., Schinke, T., Bindl, R., Wehner, T., Rapp, A. E., Haffner‐Luntzer, M., Nemitz, C., Liedert, A., Amling, M., & Ignatius, A. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084232 · Cited by 59
“Furthermore, loss of SOST, a negative regulator of osteoblast activity produced by osteocytes, which binds to LRP5 and inhibits Wnt signaling [10], leads to high bone mass disorders, such as van Buchem disease or sclerostosis [10,11].”
BackgroundGoggin, P., Zygalakis, K. C., Oreffo, R. O. C., & Schneider, P. (2016) · European Cells and Materials · doi:10.22203/ecm.v031a18 · Cited by 56
Гордеева, О. Ф. (2019) · Cells · doi:10.3390/cells8121500 · Cited by 60
“BMP signaling is inhibited by several antagonists, such as Noggin [29], Chordin [30], Twisted gastrulation [31], Cerberus [32], Gremlin 1 and 2 [33], and Sclerostin [34], using ligand-receptor interaction blocking mechanisms.”
BackgroundSimmons, D. G., & Kennedy, T. G. (2002) · Biology of Reproduction · doi:10.1095/biolreprod.102.006858 · Cited by 56
“The conservation of the specific pattern of nine amino acids, eight cystines and a glycine, is consistent with USAG-1 being in a class of secreted proteins that contain the cystine knotlike motif; these include the transforming growth factor-b superfamily, the Norrie disease protein, the mucins, and von Willebrand fac…”
BackgroundZarrinkalam, M. R., Mulaibrahimovic, A., Atkins, G. J., & Moore, R. J. (2011) · Osteoporosis International · doi:10.1007/s00198-011-1672-4 · Cited by 56
“Osteocytes are important cells in regulating skeletal remodeling in the human skeleton [5] and consequently regulating bone mass [ 6 , 7]. Osteocytes within the bone matrix comprise 90–95% of all bone cells in the adult human skeleton.”
BackgroundThe Therapeutic Potential of the Wnt Signaling Pathway in Bone Disorders
Wagner, E. R., Zhu, G., Zhang, B., Luo, Q., Shi, Q., Huang, E., Gao, Y., Gao, J., Kim, S. H., Rastegar, F., et al. (2011) · Current Molecular Pharmacology · doi:10.2174/1874-470211104010014 · Cited by 69
“The autosomal recessive diseases Sclerostosis and Van Buchen disease form secondary to homozygous mutations of Sost encoding the secreted protein sclerostin [74, 75].”
Kamiya, N., Kaartinen, V., & Mishina, Y. M. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.09.060 · Cited by 55
“In humans, loss-of-function and hypomorphic mutations in SOST cause sclerosteosis [33] and Van Buchem disease [34], respectively, with a high bone mass (HBM) phenotype.”
Background
Metadata
- Authors
- Balemans, W.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Balemans, W.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-03-01
- Volume
- 10
- Issue
- 5
- Pages
- 537-543
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2119934014
- Cited by
- 1,147
- References
- 36
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 34 · 2023: 33 · 2022: 41 · 2021: 64 · 2020: 60 · 2019: 49 · 2018: 48 · 2017: 70 · 2016: 71 · 2015: 74 · 2014: 72 · 2013: 83 · 2012: 68
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Universiteit Antwerpen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- sclerosteosis, SOST gene, sclerostin, bone mineral density, bone formation regulation, van Buchem disease, positional cloning, nonsense mutation, splice site mutation, loss-of-function mutations, osteoporosis treatment, consanguineous family
- MeSH terms
- Amino Acid Sequence, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 17, DNA Mutational Analysis, Genetic Markers, Humans, Genetic Linkage, Molecular Sequence Data, Osteochondrodysplasias, Protein Conformation, Proteins, RNA, Messenger, Bone Density, Sequence Homology, Amino Acid, DNA, Complementary, Bone Morphogenetic Proteins, Adaptor Proteins, Signal Transducing
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