Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men.
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.
Crabbe
Patricia
P
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. Patricia.Crabbe@UGent.be
Balemans
Wendy
W
Willaert
Andy
A
van Pottelbergh
Inge
I
Cleiren
Erna
E
Coucke
Paul J
PJ
Ai
Minrong
M
Goemaere
Stefan
S
van Hul
Wim
W
de Paepe
Anne
A
Kaufman
Jean-Marc
JM
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
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