Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Bone. 2010 Apr;46(4):940-5. doi: 10.1016/j.bone.2009.12.022. Epub 2010 Jan 4.
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.
最近的研究证实，低密度脂蛋白受体相关蛋白 5 基因（LRP5）在骨量积累和成人骨质疏松性骨折易感性中起作用。本研究评估了 LRP5 变异是否与儿童骨折有关。
在一项关于儿童骨折的流行病学研究中，纳入了 1390 例连续的芬兰急性骨折患儿，我们招募了易骨折的 4-16 岁儿童，这些儿童在 10 岁之前有至少两次低能量长骨骨折史或在 16 岁之前有三次低能量长骨骨折史，和/或至少一次低能量椎体压缩性骨折。共有 72 名（5.2%）儿童符合这些纳入标准；其中 66 名儿童获得了 DNA 样本。对 LRP5 基因的所有 23 个外显子和外显子-内含子边界进行测序；在 235 名健康的芬兰对照样本中分析了鉴定出的变体。
测序显示 15 个编码区错义或无义突变，其功能后果未知。未发现明显的功能丧失突变，如缺失、插入或导致提前终止密码子或改变剪接的突变。对 9 个有新的或罕见变异的家系的先证者和父母进行表型分析，以及对父母进行基因分型，结果显示没有任何 LRP5 变异与骨折明显相关。
我们的研究表明，在儿童中，LRP5 突变不是导致骨折增加的常见原因。观察到的罕见 LRP5 变体可能与不利的环境和其他遗传因素一起导致儿童骨折，但需要进一步研究以确认其功能意义和可能发生的生物学途径。我们的发现表明，在复发性骨折的儿童中，系统的 LRP5 筛查没有必要。
