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Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (\u03b2-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with <jats:italic>LRP5<\/jats:italic> gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1\u20134: 1.877\u00a0g\/cm<jats:sup>2<\/jats:sup>, Z-score: 5.8; total hip: 1.705\u00a0g\/cm<jats:sup>2<\/jats:sup>, Z-score: 5.7), slightly increased P1NP (87.0\u00a0ng\/mL) and \u03b2-CTX (0.761\u00a0ng\/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in <jats:italic>LRP5<\/jats:italic> gene, which were mutation in exon 3 (c.586\u00a0T\u2009&gt;\u2009G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C\u2009&gt;\u2009A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in <jats:italic>LRP5<\/jats:italic> were detected in 113 patients from 33 families. Hotspot mutations included c.724G\u2009&gt;\u2009A, c.512G\u2009&gt;\u2009T and c.758C\u2009&gt;\u2009T. Furthermore, mutations in the exon 3 of <jats:italic>LRP5<\/jats:italic> may cause severe phenotypes. <jats:italic>LRP5<\/jats:italic> gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type \u0399 (ADO \u0399), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.<\/jats:p>","DOI":"10.1007\/s00438-023-02008-2","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:04:32Z","timestamp":1679922272000},"page":"683-692","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review"],"prefix":"10.1007","volume":"298","author":[{"given":"Dichen","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingna","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weibo","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Xing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-2252","authenticated-orcid":false,"given":"Mei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"issue":"12","key":"2008_CR1","doi-asserted-by":"publisher","first-page":"4946","DOI":"10.1128\/MCB.25.12.4946-4955.2005","volume":"25","author":"M Ai","year":"2005","unstructured":"Ai M, Holmen SL, Van Hul W et al (2005) Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. 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