Heterozygous Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene Are Associated With Primary Osteoporosis in Children

Authors

  • Heini Hartikka,

    1. Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
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  • Outi Mäkitie,

    1. Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Canada
    2. Hospital for Children and Adolescents, Division of Endocrinology, Helsinki University Hospital, Helsinki, Finland
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  • Minna Männikkö,

    1. Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
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  • Andrea S Doria,

    1. Division of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • Alan Daneman,

    1. Division of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • William G Cole,

    1. Division of Orthopaedic Surgery, Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • Leena Ala-Kokko MD,

    Corresponding author
    1. Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
    2. Center for Gene Therapy and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
    • Department of Medical Biochemistry and Molecular Biology, Oulu University Hospital, Aapistie 3B, 90220 Oulu, Finland
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  • Etienne B Sochett

    1. Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • The authors have no conflict of interest.

Abstract

Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis.

Introduction: The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosis-pseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility.

Materials and Methods: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations.

Results and Conclusions: No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.

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