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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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“Thus, deletion of the gene encoding sclerostin is associated with increased bone mass [108,109], and forced overexpression of sclerostin causes osteoporosis [107].”
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“Of interest, subsequent genetic studies revealed the existence of different mutations within the SOST gene, encoding sclerostin, or downstream the same gene as a cause of sclerosteosis and van Buchem’s disease, respectively, two rare autosomalrecessive endosteal hyperostosis syndromes with high bone mass and absence o…”
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Sharma, G., Sharma, A. R., Seo, E.-M., & Nam, J. (2015) · BioMed Research International · doi:10.1155/2015/847529 · Cited by 23
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Baron, R. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.207 · Cited by 23
“Mutations in the gene encoding sclerostin, an osteocyte-derived Wnt antagonist, cause sclerosteosis or van Buchem disease, two high-bone-mass syndromes”
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“Mutations of the SOST gene, which encodes for sclerostin, result in progressive pathological bone thickening and clinical conditions named sclerosteosis and van Buchem's disease (Balemans et al., 2001; Loots et al., 2005).”
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“Loss-of-function mutations of sclerostin lead to a rare heritable disease named sclerosteosis, which is characterized by overgrowth of mechanically competent bone.(14,15) Inhibition of sclerostin by gene knockout (KO) or monoclonal antibodies also results in this high bone mass phenotype.”
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“Sclerostin is a secreted glycoprotein that is encoded by the SOST gene [1,2].”
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“Although the biochemical properties of this protein have not been fully understood, homozygous mutations of this gene in humans result in sclerostosis, an autosomal recessive skeletal dysplasia characterized by excessive bone overgrowth [83].”
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“Interestingly, the SOST gene is found to be also expressed in other tissues and organs and, besides bone, primarily in heart, lung, aorta, and kidney [128,129].”
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Riddle, R. C. (2022) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2022.100433 · Cited by 21
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Next-generation sequencing: a frameshift in skeletal dysplasia gene discovery
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“to be responsible for sclerosteosis [11, 12] and Van Buchem disease [13, 14], both rare skeletal dysplasias associated with high bone mass.”
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“Analysis of rare populations with extraordinarily high bone mass (but otherwise normal physiology) has led to the identification of a loss-of-function mutation in a secreted protein, termed SOST (sclerostin), that regulates bone formation [18].”
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Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice
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“Two rare human bone disorders, sclerosteosis and van Buchem disease, are characterized by dramatic increases in bone mineral density (BMD) and have been genetically traced to mutations in the Sost gene locus, which codes for sclerostin [1,2].”
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“osis (MIM 269500), which are both characterized by an enormously increased bone mass as a consequence of unrestrained Wnt/b-catenin signaling [16–21].”
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“On the basis of the presence of a cystine-knot motif in its structure, sclerostin has been ranked in the DAN (differential screening selected gene abberative in neuroblastoma) family of secreted glycoproteins that share the ability to antagonize bone morphogenetic protein (BMP) activity.(1,3) As sclerostin inhibits BM…”
BackgroundTargeting Sclerostin in Postmenopausal Osteoporosis: Focus on Romosozumab and Blosozumab
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“In humans, a lack of expression, or reduced expression of sclerostin, results in the sclerosing bone dysplasias, sclerosteosis and van Buchem disease that are associated with osteoblastic hyperactivity, progressive skeletal overgrowth, with clinical manifestation of a high bone mass and craniofacial abnormalities.(6,7…”
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Cortical bone adaptation to a moderate level of mechanical loading in male Sost deficient mice
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“Briefly, the algorithm involves the following steps: (1) geometrical registration of images, (2) thresholding to extract the bone region, using the same global threshold mentioned above, (3) segmentation to exclude mineralized tissue present in the medullary cavity inside the VOI, (4) labeling regions of quiescent, ne…”
MethodXu, C., Xie, X., Zhao, H., Wu, Y., Wang, J., & Feng, J. Q. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.721775 · Cited by 19
“On the other hand, there was a drastic increase of SOST, an osteocyte marker and potent inhibitor of Wnt signaling (Balemans et al., 2001) in the early cKO group.”
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“Postnatal homozygous mutant animals display a number of distinct phenotypes [25] [26], including changes in bone density which are described in this study.”
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Fielden, M. R., Ward, L. D., Minocherhomji, S., Nioi, P., Lebrec, H. N., & Jacobson‐Kram, D. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.11.005 · Cited by 19
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Sclerosteosis: Report of type 1 or 2 in three Indian Tamil families and literature review
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The promise of sclerostin inhibition for the treatment of osteoporosis
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“A lack of sclerostin expression in mature osteocytes results in a progressive, generalized, massive bone mass increase due to high bone formation in humans and mice (1-3), suggesting that inhibition of this secreted glycoprotein might restore bone mass and thus strength to the osteoporotic skeleton.”
BackgroundResultInfluentialSclerostin expression in bone tumours and tumour‐like lesions
Inagaki, Y., Hookway, E. S., Kashima, T. G., Munemoto, M., Tanaka, Y., Hassan, A. B., Oppermann, U. C. T., & Athanasou, N. A. (2016) · Histopathology · doi:10.1111/his.12953 · Cited by 19
“In humans, SOST mRNA is expressed in the heart, aorta, and liver, and at high levels in the kidney.(10,11,16,17) In adult mouse and human bone, sclerostin expression is restricted to osteocytes, being localized around osteocyte lacunae and in dendritic processes in osteocyte canaliculi.”
BackgroundDickkopf-1 as a potential therapeutic target in Paget's disease of bone
McCarthy, H. S., & Marshall, M. J. E. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903525720 · Cited by 19
“Mutations that result in insensitivity to sclerostin, result in rare high-bone-mass disorders such as the autosomal recessive disorder sclerosteosis [55] or van Buchem disease [56].”
BackgroundTherapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis
Shah, A. A., Chand, D., Ahamad, S., Porwal, K., Chourasia, M. K., Mohanan, K., Srivastava, K. R., & Chattopadhyay, N. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116587 · Cited by 18
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“Insight into sclerostin’s function in bone came from two main clinical populations: sclerosteosis patients who harbor loss-of-function mutations in the SOST gene,(5,6) and hyperostosis corticalis patients who harbor gain-of function mutations in the sclerostin target LRP5.”
BackgroundLim, S. Y., & Bolster, M. B. (2022) · International Journal of Women s Health · doi:10.2147/ijwh.s315184 · Cited by 18
“Patients with these conditions have high bone mass characterized by progressive generalized osteosclerosis in the skull, mandible, ribs, clavicles, and long bones.(10,11) Given this sclerostin deficiency, patients with sclerosteosis and Van Buchem’s disease demonstrate a very low fracture risk due to increased bone ma…”
BackgroundPhysiopathology of Osteoporosis: Nursing Involvement and Management
Valenzuela-Martínez, S., Ramı́rez-Expósito, M. J., Carrera-González, M. P., & Martı́nez-Martos, J. M. (2023) · Biomedicines · doi:10.3390/biomedicines11041220 · Cited by 24
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Building bone with a SOST-PTH partnership
Sims, N. A. (2010) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.53 · Cited by 18
“In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis,((12)) trabecular bone volume was more than double that of wild-type mice.”
BackgroundTHE FETAL MUSCULOSKELETAL SYSTEM
Gonçalves, L. F., Kusanovic, J. P., Gotsch, F., Espinoza, J., & Romero, R. J. (2008) · Elsevier eBooks · doi:10.1016/b978-1-4160-3264-9.50016-1 · Cited by 18
Competitive blocking of LRP4–sclerostin binding interface strongly promotes bone anabolic functions
Katchkovsky, S., Chatterjee, B., Abramovitch-Dahan, C.-V., Papo, N., & Levaot, N. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04127-2 · Cited by 18
Gonciulea, A. R., & de Beur, S. M. J. (2015) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-015-9316-1 · Cited by 18
“phenotype is very similar but less severe than in sclerostosis, with normal stature and no syndactyly [55].”
BackgroundRegulation of Sclerostin Expression by Paracrine and Endocrine Factors
Sims, N. A., & Chia, L. Y. (2011) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-011-9121-7 · Cited by 18
“While most work to date has focused on the osteocytic expression of sclerostin, sclerostin mRNA has been detected in other organs in human and mouse, including kidney, lung and heart [1, 3, 6], in vascular smooth muscle cells [13] and human and murine chondrocytes [3, 14].”
BackgroundValidation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments
Drake, M. T., Fenske, J. S., Blocki, F. A., Zierold, C., Appelman‐Dijkstra, N. M., Papapoulos, S. E., & Khosla, S. (2018) · Bone · doi:10.1016/j.bone.2018.03.013 · Cited by 18
“Mutations in SOST, the gene encoding sclerostin, have been identified as the causative defect in patients with the rare high bone mass disorder sclerosteosis [2, 3].”
BackgroundReptiles in Space Missions: Results and Perspectives
Gulimova, V. I., Proshchina, A. E., Kharlamova, A. S., Krivova, Y. S., Barabanov, V., Berdiev, R. K., Асадчиков, В. Е., Buzmakov, A. V., Zolotov, D. A., & Saveliev, S. V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123019 · Cited by 20
“At the beginning of the current century it was revealed that deletions in the Sost gene lead to bone overgrowth of the skull, mandible, and/or hand digits [130,131].”
BackgroundGregson, C. L., Poole, K. E. S., McCloskey, E. V., Duncan, E. L., Rittweger, J., Fraser, W. D., Smith, G. D., & Tobias, J. H. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3958 · Cited by 16
Janeczek, A. A., Tare, R. S., Scarpa, E., Moreno-Jiménez, I., Rowland, C. A., Jenner, D. C., Newman, T. A., Oreffo, R. O. C., & Evans, N. D. (2015) · Stem Cells · doi:10.1002/stem.2241 · Cited by 16
Yamamoto, T., Ikegame, M., Hirayama, J., Kitamura, K.-I., Tabuchi, Y., Furusawa, Y., Sekiguchi, T., Endo, M., Mishima, H., Seki, A., et al. (2020) · Biomedical Research · doi:10.2220/biomedres.41.279 · Cited by 19
“Mutations in Sost are associated with bone diseases characterized by high bone mass, such as sclerosteosis and Van Buchem disease (Balemans et al. 2001; Brunkow et al. 2001; Balemans et al. 2002; Staehling-Hampton et al. 2002).”
BackgroundWatanabe, T., Tamamura, Y., Hoshino, A., Makino, Y., Kamioka, H., Amagasa, T., Yamaguchi, A., & Iimura, T. (2012) · Bone · doi:10.1016/j.bone.2012.06.019 · Cited by 17
“Loss-of-function mutations in the SOST gene, which encodes sclerostin, cause sclerosteosis or Van Buchem disease, which are both associated with a high bone mass and thickened bone [34–37], and are consistentwith the phenotype observed following targeted deletion of themouse SOST [38].”
BackgroundProvot, S., Schipani, E., Wu, J. Y., & Kronenberg, H. M. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-415853-5.00006-6 · Cited by 18
Treatment with anti‐Sclerostin antibody to stimulate mandibular bone formation
Tamplen, M. L., Fowler, T. W., Markey, J., Knott, P. D., Suva, L. J., & Alliston, T. N. (2018) · Head & Neck · doi:10.1002/hed.25128 · Cited by 17
“Sclerostin was identified by studying the loss-of-function mutation in patients with the rare genetic disorder Sclerosteosis.(1,4,5,7) Sclerosteosis is characterized by extremely high bone mass throughout the skeleton, tall stature, and enlarged jaws.”
BackgroundInduction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism
Kang, K. S., Hong, J. M., Horan, D. J., Lim, K., Bullock, W. A., Bruzzaniti, A., Hann, S., Warman, M. L., & Robling, A. G. (2018) · Bone · doi:10.1016/j.bone.2018.10.007 · Cited by 17
New treatments of osteoporosis
Langdahl, B. L. (2015) · Osteoporosis and Sarcopenia · doi:10.1016/j.afos.2015.07.007 · Cited by 17
Genetics of Osteoporosis: Perspectives for Personalized Medicine
Li, W., Hou, S.-X., Yu, B., Jin, D., Férec, C., & Chen, J. (2010) · Personalized Medicine · doi:10.2217/pme.10.55 · Cited by 17
How genomics has informed our understanding of the pathogenesis of osteoporosis
Johnson, M. L., Lara, N., & Kamel, M. A. (2009) · Genome Medicine · doi:10.1186/gm84 · Cited by 17
Zeng, J., Xiao, Q. F., Li, X., & Chen, J. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4941 · Cited by 16
High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench
Bergen, D. J. M., Maurizi, A., Formosa, M. M., McDonald, G. L. K., El‐Gazzar, A., Hassan, N., Brandi, M. L., Riancho, J. A., Rivadeneira, F., Ntzani, E., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4715 · Cited by 17
“A prominent example of such success was the discovery of loss-of-function (LoF) mutations in SOST encoding sclerostin in families with sclerosteosis (OMIM 269500) and van Buchem disease (OMIM 239100), two severe HBM conditions.((6-8)) A concerted multidisciplinary research effort then unraveled the precise function an…”
BackgroundFlorio, M., Kostenuik, P. J., Stolina, M., Asuncion, F., Grisanti, M. S., Ke, H. Z., & Ominsky, M. S. (2023) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.22.01092 · Cited by 17
Sost Deficiency does not Alter Bone’s Lacunar or Vascular Porosity in Mice
Mosey, H., Núñez, J. A., Goring, A., Clarkin, C., Staines, K. A., Lee, P. D., Pitsillides, A. A., & Javaheri, B. (2017) · Frontiers in Materials · doi:10.3389/fmats.2017.00027 · Cited by 15
“Previous studies reported that the Wnt signaling and SCLEROSTIN regulate bone remodeling (Balemans et al., 2001; Van Wesenbeeck et al., 2003), influence pre-osteoblast differentiation and proliferation (Kato et al., 2002) and osteoblast-to-osteocyte transition in vitro (Atkins et al., 2011).”
BackgroundInfluentialAdvances in osteoporosis from 1970 to 2018
Gallagher, J. C. (2018) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000001263 · Cited by 16
Bone Cell Communication Factors Provide a New Therapeutic Strategy for Osteoporosis
Kim, J. H., & Kim, N. (2020) · Chonnam Medical Journal · doi:10.4068/cmj.2020.56.2.94 · Cited by 17
Sclerostin and the Unloading of Bone
Suva, L. J. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090815 · Cited by 16
“ated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth.((4,5)) A deletion downstream of this gene, which results in reduced sclero-”
BackgroundTIEG and estrogen modulate SOST expression in the murine skeleton
Subramaniam, M., Pitel, K. S., Bruinsma, E. S., Monroe, D. G., & Hawse, J. R. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26211 · Cited by 16
“Mutations in, or deletion of, the SOST gene are known to cause a high bone mass phenotype in mice and humans (Balemans et al., 2001; Brunkow et al., 2001; Li et al., 2008).”
BackgroundMace, M. L., Gravesen, E., Nordholm, A., Egstrand, S., Morevati, M., Ølgaard, K., & Lewin, E. (2022) · JBMR Plus · doi:10.1002/jbm4.10610 · Cited by 15
“Osteocytes secrete sclerostin, which is an essential factor in balancing bone formation and resorption.((40,43,44)) In the present study we showed upregulation of Sost gene in the calcified aorta from uremic rats, which also secreted sclerostin in high amounts, like our previous results.”
ResultLRP5, Bone Mass Polymorphisms and Skeletal Disorders
Littman, J., Yang, W., Olansen, J., Phornphutkul, C., & Aaron, R. K. (2023) · Genes · doi:10.3390/genes14101846 · Cited by 16
Martin, T. J., & Seeman, E. (2023) · Neurospine · doi:10.14245/ns.2346966.483 · Cited by 17
“85 Physiologically, rapid reductions in sclerostin could mediate the reduction in refilling of an excavated resorption site so that it does not overfill.”
BackgroundJeon, I., Park, S. B., Moon, B. J., Choi, M., Kuh, S. U., & Kim, J. (2024) · Neurospine · doi:10.14245/ns.2347256.628 · Cited by 15
John, H. C. S., Hansen, S. J., & Pike, J. W. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.09.005 · Cited by 15
Anti-sclerostin – is there an indication?
Larsson, S. (2016) · Injury · doi:10.1016/s0020-1383(16)30008-0 · Cited by 15
Kristianto, J., Johnson, M. G., Afzal, R., & Blank, R. D. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2016.09.014 · Cited by 15
“Mice in which Sost (the mouse gene encoding SOST) has been knocked out display increased bone mass, mimicking the human sclerosteosis phenotype.(80,81)”
BackgroundYooin, W., Saenjum, C., Ruangsuriya, J., & Jiranusornkul, S. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1599427 · Cited by 15
Sclerostin within the chronic kidney disease spectrum
Bouquegneau, A., Evenepoel, P., Paquot, F., Malaise, O., Cavalier, E., & Delanaye, P. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.12.008 · Cited by 17
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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