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The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mousemodels with bone-specific inactivation or overexpression, but mice carrying disease-causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced thismutation into themurine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1+\/R235W and Wnt1R235W\/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild-type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1+\/R235W mice, thereby underscoring their value as amodel of WNT1-dependent EOOP. Importantly, when we treated wild-type and Wnt1+\/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased cortical thickness in themutant mice. Our data demonstrate the pathogenicity of the WNT1-R235W mutation, confirm that controlling skeletal integrity is the primary physiological function of Wnt1, and suggest that osteoanabolic treatment with teriparatide should be applicable for individuals with WNT1-dependent EOOP. \u00a9 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4043","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T09:46:16Z","timestamp":1588671976000},"page":"1726-1737","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-0983","authenticated-orcid":false,"given":"Timur Alexander","family":"Yorgan","sequence":"first","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Rolvien","sequence":"additional","affiliation":[{"name":"Department of Orthopedics University Medical Center Hamburg-Eppendorf Hamburg Germany"},{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"St\u00fcrznickel","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele","family":"Vollersen","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Lange","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Sharaf","sequence":"additional","affiliation":[{"name":"Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH) University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meliha","family":"Karsak","sequence":"additional","affiliation":[{"name":"Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH) University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"David","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Oheim","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2382-8348","authenticated-orcid":false,"given":"Michael","family":"Amling","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-0177","authenticated-orcid":false,"given":"Thorsten","family":"Schinke","sequence":"additional","affiliation":[{"name":"Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf Hamburg 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