title: Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men.
abstract: We studied whether the LRP5 gene contributes to the clinical phenotype of IO in men. Mutation analysis in 66 IO men revealed a range of sequence variants, of which two missense variants were shown to be of functional relevance.
  
  
  BACKGROUND
  Mutations in the LDL receptor-related protein 5 (LRP5) gene have been associated with extreme bone phenotypes, which makes LRP5 a plausible candidate gene for idiopathic osteoporosis (IO).
  
  
  METHODS
  In 66 men with IO, all 23 exons and exon-intron boundaries of the LRP5 gene were screened for mutations, and functional analyses were performed for those that were putatively involved in the phenotype.
  
  
  RESULTS
  Mutation analysis in the IO probands revealed five missense mutations, of which 1067C>T (S356L), 1364C>T (S455L), and 4609G>A (A1537T) were of potential functional significance because they were located in highly conserved regions of LRP5 and not found in a control panel. Segregation analysis in the respective families could not exclude their possible causality for IO. Furthermore, functional analyses clearly showed an inhibitory effect of mutations 1067C>T and 1364C>T on Wnt signal transduction. These effects are most likely caused by impaired LRP5 synthesis in the case of 1067C>T and failure of protein trafficking to the cell surface for 1364C>T.
  
  
  CONCLUSIONS
  For 2 of 66 IO probands, a mutation in the LRP5 gene with proven functionality was found. The findings indicate that carrying an LRP5 mutation is a risk factor for IO, but that overall, IO in men is infrequently underlied by such a mutation.
authors.affiliation: Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. Patricia.Crabbe@UGent.be
authors.forename: Patricia
authors.initials: P
authors.lastname: Crabbe
authors.forename: Wendy
authors.initials: W
authors.lastname: Balemans
authors.forename: Andy
authors.initials: A
authors.lastname: Willaert
authors.forename: Inge
authors.initials: I
authors.lastname: van Pottelbergh
authors.forename: Erna
authors.initials: E
authors.lastname: Cleiren
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Minrong
authors.initials: M
authors.lastname: Ai
authors.forename: Stefan
authors.initials: S
authors.lastname: Goemaere
authors.forename: Wim
authors.initials: W
authors.lastname: van Hul
authors.forename: Anne
authors.initials: A
authors.lastname: de Paepe
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015519:Bone Density / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000235:genetics; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D007438:Introns / Q000235:genetics; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014162:Transfection; D051155:Wnt1 Protein / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C495247:WNT1 protein, human; D051155:Wnt1 Protein