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Bone Abstracts (2013) 2 LB2 | DOI: 10.1530/boneabs.2.LB2

1Folkhälsan Institute of Genetics, Helsinki, Finland; 2Children’s Hospital, University of Helsinki, Helsinki, Finland; 3Department of Medical Biochemistry and Genetics and Department of Medicine, University of Turku, Turku, Finland; 4Department of Cell Biology and Anatomy, University of Turku, Turku, Finland; 5Sahlgrenska University Hospital, Gothenburg, Sweden; 6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; 7Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA; 8Bone and Cartilage Research Unit, University of Eastern Finland, Kuopio, Finland; 9Division of Pediatric Surgery, University of Alberta, Alberta, Edmonton, Canada; 10University of California–Los Angeles, Los Angeles, California, USA; 11University of California–San Francisco, San Francisco, California, USA.

The role of the WNT pathway in skeletal maintenance has been extensively studied since the identification of mutations in key signaling WNT mediators (LRP5 and sclerostin) in high and low bone mass phenotypes. However, the identity of the key WNT ligand that signals via LRP5/6 has remained unknown. We aimed to identify genes with a major effect on the skeleton by studying individuals and families with early-onset osteoporosis or osteogenesis imperfecta (OI).

We recruited a Finnish family with severe early-onset and dominantly inherited osteoporosis, characterized by low BMD and vertebral fractures, in ten individuals. Histomorphometry showed severe low-turnover osteoporosis with low bone formation in two adults and reduced bone remodeling in a 14-year-old boy. A genome-wide microsatellite scan, fine-mapping and targeted next-generation sequencing of the linkage region identified a single novel variant in WNT1 (p.C218G) segregating with the phenotype. We also ascertained a Laotian Hmong family with two severely affected daughters suffering from recessive OI. After exclusion of mutations in the known OI genes we performed whole-exome sequencing and identified a homozygous nonsense mutation in WNT1 (p.Ser295*) in both affected children.

The mutant WNT1C218G and WNT1S295* proteins were stable and exhibited similar cellular distribution to the wild type (wt) WNT1. In contrast with wt-WNT1, WNT1C218G and WNT1S295* did not induce significant accumulation of active β-catenin in the nucleus. Accordingly, WNT1C218G and WNT1S295* showed significantly reduced capacity to induce canonical WNT signaling in a TOPFLASH reporter assay. They also had impaired capacity to induce the WNT target gene expression and osteoblast differentiation in vitro. In expression profiling by RT-PCR we detected Wnt1 expression in mouse brain, femur and spleen but not in calvarial osteoblasts, osteoclasts or human mesenchymal stromal cells. Wnt1 was clearly expressed in bone marrow, especially in B cell lineage and hematopoietic progenitors. Using a Wnt1-Cre crossed with a reporter mice Wnt1 expression was also detected in a subset of osteocytes.

Our results suggest altered cross-talk of WNT signaling between hematopoietic and osteoblast lineage cells as the pathogenetic mechanism. These findings indicate that loss-of-function heterozygous or bi-allelic mutations in WNT1 result in early-onset osteoporosis or OI and identify WNT1 as a key WNT ligand in the regulation of bone mass.

Volume 2

6th International Conference on Children's Bone Health

Rotterdam, The Netherlands
22 Jun 2013 - 25 Jun 2013


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