Data from this study were presented at the 11th and Valedictory Workshop on Cell Biology of Bone and Cartilage in Health and Disease, March 18, 2006, Davos, Switzerland.
Version of Record online: 12 FEB 2007
Copyright © 2007 ASBMR
Journal of Bone and Mineral Research
Volume 22, Issue 5, pages 708–716, May 2007
How to Cite
Balemans, W., Devogelaer, J.-P., Cleiren, E., Piters, E., Caussin, E. and Van Hul, W. (2007), Novel LRP5 Missense Mutation in a Patient With a High Bone Mass Phenotype Results in Decreased DKK1-Mediated Inhibition of Wnt Signaling*. J Bone Miner Res, 22: 708–716. doi: 10.1359/jbmr.070211
The authors state that they have no conflicts of interest.
Published online on February 12, 2007
- Issue online: 4 DEC 2009
- Version of Record online: 12 FEB 2007
- Manuscript Accepted: 8 FEB 2007
- Manuscript Revised: 4 JAN 2007
- Manuscript Received: 18 SEP 2006
- high BMD;
- low-density lipoprotein receptor–related protein 5;
- gain-of-function mutation;
- canonical Wnt signaling;
- Dickkopf 1
We found a novel heterozygous missense mutation (M282V) in the LRP5 gene in a patient with a high bone mass phenotype. In vitro studies suggest that a reduced antagonistic effect of DKK1 on canonical Wnt signaling contributes to the molecular effect of this mutation and its pathogenic consequence.
Introduction: Gain-of-function mutations in the gene encoding LDL receptor–related protein 5 (LRP5) cause high bone mass. Recent studies revealed that a reduced inhibition of canonical Wnt signaling by Dickkopf 1 (DKK1) contributes to the pathophysiology of this disease phenotype.
Materials and Methods: We report on a 55-yr-old female patient with a high bone mass phenotype. Sequencing of exons 2–4 of the LRP5 gene was carried out to screen for disease-associated mutations in genomic DNA of the patient. The effect of the identified mutation on LRP5 membrane trafficking was studied by immunoblotting of a truncated form of LRP5. Additionally, Wnt signal activation in the absence and presence of DKK1 was assessed using a TCF4-based reporter gene assay in Saos-2 cells.
Results: Our patient presents with dense bones (Z-scores > +6), and radiographic examination showed a generalized thickening of the skeleton. BMD at the hip and lumbar spine significantly decreased through the passage to menopause, indicating no protection to bone loss. Further clinical evaluation revealed torus palatinus. Mutation analysis showed the presence of a novel heterozygous missense variant (844AG; M282V) in LRP5, located in the first β-propeller domain of the extracellular portion. Although protein secretion seemed to be impaired, this mutant was able to transduce Wnt signals at levels comparable with wildtype LRP5. We additionally observed a less efficient inhibition of canonical Wnt signaling by DKK1.
Conclusions: Like all high BMD–associated gain-of-function LRP5 mutations described thus far, the M282V variant affects an amino acid located in the first β-propeller domain, underlining the functional importance of this region in the pathophysiology of these conditions. This mutation most likely alters a region important for LRP5 modulation by DKK.