LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6
ABSTRACT Osteoblast Wnt/β‐catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low‐density lipoprotein receptor‐related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 i...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | JBMR Plus |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jbm4.10717 |
| _version_ | 1797847752641609728 |
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| author | Michael P Whyte Steven Mumm Jonathan C Baker Fan Zhang Homer Sedighi Shenghui Duan Tim Cundy |
| author_facet | Michael P Whyte Steven Mumm Jonathan C Baker Fan Zhang Homer Sedighi Shenghui Duan Tim Cundy |
| author_sort | Michael P Whyte |
| collection | DOAJ |
| description | ABSTRACT Osteoblast Wnt/β‐catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low‐density lipoprotein receptor‐related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β‐propeller of LRP5 or LRP6, thereby disassociating these cognate co‐receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle‐aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z‐scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. |
| first_indexed | 2024-04-09T18:16:25Z |
| format | Article |
| id | doaj.art-33b95b6f29a44cfba1e91ac1b29fa69e |
| institution | Directory Open Access Journal |
| issn | 2473-4039 |
| language | English |
| last_indexed | 2024-04-09T18:16:25Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | JBMR Plus |
| spelling | doaj.art-33b95b6f29a44cfba1e91ac1b29fa69e2023-04-13T03:03:15ZengWileyJBMR Plus2473-40392023-04-0174n/an/a10.1002/jbm4.10717LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6Michael P Whyte0Steven Mumm1Jonathan C Baker2Fan Zhang3Homer Sedighi4Shenghui Duan5Tim Cundy6Division of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes‐Jewish Hospital St. Louis MO USADivision of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes‐Jewish Hospital St. Louis MO USAMallinckrodt Institute of Radiology, Musculoskeletal Section Washington University School of Medicine St. Louis MO USACenter for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children – St. Louis St. Louis MO USADepartment of Plastic Surgery Washington University School of Medicine at St. Louis Children's Hospital St. Louis MO USADivision of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes‐Jewish Hospital St. Louis MO USAFaculty of Medical & Health Sciences University of Auckland Auckland New ZealandABSTRACT Osteoblast Wnt/β‐catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low‐density lipoprotein receptor‐related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β‐propeller of LRP5 or LRP6, thereby disassociating these cognate co‐receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle‐aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z‐scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.https://doi.org/10.1002/jbm4.10717BONE DENSITYBONE MODELINGDICKKOPF1DXAENDOSTEUMEXOSTOSIS |
| spellingShingle | Michael P Whyte Steven Mumm Jonathan C Baker Fan Zhang Homer Sedighi Shenghui Duan Tim Cundy LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 JBMR Plus BONE DENSITY BONE MODELING DICKKOPF1 DXA ENDOSTEUM EXOSTOSIS |
| title | LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 |
| title_full | LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 |
| title_fullStr | LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 |
| title_full_unstemmed | LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 |
| title_short | LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6 |
| title_sort | lrp6 high bone mass characterized in two generations harboring a unique mutation of low density lipoprotein receptor related protein 6 |
| topic | BONE DENSITY BONE MODELING DICKKOPF1 DXA ENDOSTEUM EXOSTOSIS |
| url | https://doi.org/10.1002/jbm4.10717 |
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