{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:48:44Z","timestamp":1782398924016,"version":"3.54.5"},"reference-count":24,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Research Foundation - Flanders","doi-asserted-by":"publisher","award":["G031915N"],"award-info":[{"award-number":["G031915N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Research Foundation - Flanders","doi-asserted-by":"publisher","award":["12A3814N"],"award-info":[{"award-number":["12A3814N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Methusalem - OEC grant - &quot;GENOMED&quot;","award":["FFB190208"],"award-info":[{"award-number":["FFB190208"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third \u03b2-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first \u03b2-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first \u03b2-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.<\/jats:p>","DOI":"10.3390\/genes13010080","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third \u03b2-Propeller Domain Can Cause Sclerosteosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Yentl","family":"Huybrechts","sequence":"first","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eveline","family":"Boudin","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6715-9241","authenticated-orcid":false,"given":"Gretl","family":"Hendrickx","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Steenackers","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neveen","family":"Hamdy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, 2332 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Mortier","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9498-5979","authenticated-orcid":false,"given":"Guillermo","family":"Mart\u00ednez D\u00edaz-Guerra","sequence":"additional","affiliation":[{"name":"Endocrinology and Nutrition Resident, 12 de Octubre University Hospital, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milagros Sierra","family":"Bracamonte","sequence":"additional","affiliation":[{"name":"Endocrinology and Nutrition Resident, 12 de Octubre University Hospital, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-127X","authenticated-orcid":false,"given":"Natasha M.","family":"Appelman-Dijkstra","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, 2332 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5065-7858","authenticated-orcid":false,"given":"Wim","family":"Van Hul","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1399-0004.1977.tb01269.x","article-title":"Sclerosteosis\u2014An autosomal recessive disorder","volume":"11","author":"Beighton","year":"1977","journal-title":"Clin. 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