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Molecular and Cellular Biology, June 2005, p. 4946-4955, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4946-4955.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Minrong Ai,1 Sheri L. Holmen,2 Wim Van Hul,3 Bart O. Williams,2 and Matthew L. Warman1*

Department of Genetics and Center for Human Genetics, Case School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio,1 Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan,2 Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium3

Received 7 January 2005/ Returned for modification 21 January 2005/ Accepted 16 March 2005

The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical Wnt signaling pathway, has been implicated in human disorders of low and high bone mass. Loss-of-function mutations cause the autosomal recessive osteoporosis-pseudoglioma syndrome, and heterozygous missense mutations in families segregating autosomal dominant high bone mass (HBM) phenotypes have been identified. We expressed seven different HBM-LRP5 missense mutations to delineate the mechanism by which they alter Wnt signaling. None of the mutations caused activation of the receptor in the absence of ligand. Each mutant receptor was able to reach the cell surface, albeit at differing amounts, and transduce exogenously supplied Wnt1 and Wnt3a signal. All HBM mutant proteins had reduced physical interaction with and reduced inhibition by DKK1. These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations' physiologic effects is via reduced affinity to and inhibition by DKK1.

* Corresponding author. Mailing address: Department of Genetics, BRB-719, Case School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106. Phone: (216) 368-4919. Fax: (216) 368-5857. E-mail: mlw14{at}case.edu.

Molecular and Cellular Biology, June 2005, p. 4946-4955, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4946-4955.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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