Open Access Highly Accessed Research article

Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity

Johanna Korvala1, Harald Jüppner2, Outi Mäkitie3, Etienne Sochett4, Dirk Schnabel5, Stefano Mora6, Cynthia F Bartels7, Matthew L Warman8, Donald Deraska9, William G Cole10, Heini Hartikka111, Leena Ala-Kokko112 and Minna Männikkö113*

Author Affiliations

1 Oulu Center for Cell-Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

2 Departments of Medicine and Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

3 Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland

4 Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

5 Department for Pediatric Endocrinology and Diabetes, Otto-Heubner-Centrum für Kinder- und Jugendmedizin, Charite, University Medicine Berlin, Berlin, Germany

6 Laboratory of Pediatric Endocrinology, BoNetwork, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy

7 Case Western Reserve University, Department of Genetics, Cleveland, OH, USA

8 Orthopaedic Research Laboratories, Children's Hospital Boston, Boston, MA, USA

9 Department of Medicine, Winchester Hospital, Winchester, MA, USA

10 Division of Orthopaedic Surgery, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

11 Department of Surgery, North Karelia Central Hospital, Joensuu, Finland

12 Connective Tissue Gene Tests, Allentown, PA, USA

13 Department of Medical Biochemistry and Molecular Biology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland

For all author emails, please log on.

BMC Medical Genetics 2012, 13:26  doi:10.1186/1471-2350-13-26

Published: 10 April 2012



Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here.


LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b).


Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002).


Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.