Low-density lipoprotein receptor-related protein 5 (LRP5) variation in fracture prone children

Recent studies have confirmed that the low-density lipoprotein receptor-related protein 5 gene (LRP5), plays a role in bone mass accrual and in susceptibility to osteoporotic fractures in adults. This study evaluated whether LRP5 variation is implicated in childhood fractures.

During an epidemiological study on childhood fractures, comprising 1390 consecutive Finnish children with an acute fracture, we recruited fracture-prone 4-16 years old children, who had a history of at least two low-energy long bone fractures before age 10 years or three low-energy long bone fractures before age 16 years, and/or at least one low-energy vertebral compression fracture. A total of 72 (5.2%) children fulfilled these inclusion criteria; DNA samples were obtained for 66 of them. All 23 exons and exon-intron boundaries of the LRP5 gene were sequenced; the identified variants were analyzed in 235 healthy Finnish control samples.

Sequencing revealed 15 coding region missense or silent variants with unknown functional consequences. No obvious loss-of-function mutations such as deletions, insertions, or changes resulting in premature termination codon or altered splicing were identified. Phenotyping of the proband and parents, and genotyping of the parents, in 9 families with novel or rare variants showed no obvious correlation between any of the LRP5 variants and fractures.

Our study shows that in children LRP5 mutations are not a common cause of increased fractures. The observed rare LRP5 variants may together with unfavorable environmental and other genetic factors contribute to childhood fractures, but further studies are needed to confirm their functional significance and biological pathways through which this may occur. Our findings suggest that systematic LRP5 screening is not indicated in children with recurrent fractures.