title: Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children.
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.
  
  
  BACKGROUND
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
authors.forename: Heini
authors.initials: H
authors.lastname: Hartikka
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.forename: Minna
authors.initials: M
authors.lastname: Männikkö
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Doria
authors.forename: Alan
authors.initials: A
authors.lastname: Daneman
authors.forename: William G
authors.initials: WG
authors.lastname: Cole
authors.forename: Leena
authors.initials: L
authors.lastname: Ala-Kokko
authors.forename: Etienne B
authors.initials: EB
authors.lastname: Sochett
mesh_terms: D000293:Adolescent; D002648:Child; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D016368:Frameshift Mutation; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000097:blood* / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D012313:RNA; D003094:Collagen