Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations
Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations
复制标题
DOI：
10.1016/j.bone.2014.06.041
复制
发表时间：
2014-10-01
期刊：
影响因子：
4.1
通讯作者：
Rauch, Frank
中科院分区：
文献类型：
--
作者：
Palomo, Telma;Al-Jallad, Hadil;Rauch, Frank
最近的报道表明，WNT 1的纯合或复合杂合突变可引起严重的骨脆性，类似于成骨不稳，而杂合WNT 1突变已在显性早发性骨质疏松症的成人中发现。在此，我们评估了WNT 1突变对4名隐性严重骨脆性患儿和杂合子家族成员的影响。使用Topflash荧光素酶报告系统的体外研究表明，在这些家族中观察到的两个WNT 1错义突变p.Cys143Phe和p.Val355Phe使WNT 1刺激WNT信号传导的能力降低了> 90%。髂骨样本的分析显示，骨矿化密度分布（材料骨特性的指标）无重大异常，而骨矿化密度向更高方向的转变是由COL 1A 1/COL 1A 2突变引起的经典成骨异常的特征。通过双能X线吸收法测定，静脉注射双膦酸盐治疗4例纯合子或复合杂合子WNT 1突变儿童与腰椎区域骨密度z评分增加相关，但其效果小于先前报道的经典成骨不全儿童。WNT 1杂合突变的家族成员倾向于低骨量。这些杂合子个体中有三个有脊椎骨折的放射学征象。这些观察结果表明，需要更有效的治疗方法与隐性WNT 1相关的骨脆性的儿童和骨质疏松症的系统检查是必要的WNT 1突变携带者在这些家庭。(C)2014爱思唯尔公司All rights reserved.
Recent reports have shown that homozygous or compound heterozygous mutations in WNT1 can give rise to severe bone fragility resembling osteogenesis imperfecta, whereas heterozygous WNT1 mutations have been found in adults with dominant early-onset osteoporosis. Here we assessed the effects of WNT1 mutations in four children with recessive severe bone fragility and in heterozygous family members. In vitro studies using the Topflash luciferase reporter system showed that two WNT1 missense mutations that were observed in these families, p.Cys143Phe and p.Val355Phe, decreased the ability of WNT1 to stimulate WNT signaling by >90%. Analyses of iliac bone samples revealed no major abnormalities in bone mineralization density distribution, an indicator of material bone properties, whereas a shift towards higher bone mineralization density is characteristic of classical osteogenesis imperfecta caused by mutations in COL1A1/COL1A2. Intravenous bisphosphonate treatment of four children with homozygous or compound heterozygous WNT1 mutations was associated with increasing lumbar spine areal bone mineral density z-scores, as measured by dual energy X-ray absorptiometry, but the effect was smaller than what had previously been reported for children with classical osteogenesis imperfecta. Family members with heterozygous WNT1 mutation tended to have low bone mass. Three of these heterozygous individuals had radiographic signs of vertebral fractures. These observations suggest that more effective treatment approaches are needed for children with recessive WNT1-related bone fragility and that a systematic work-up for osteoporosis is warranted for WNT1 mutation carriers in these families. (C) 2014 Elsevier Inc. All rights reserved.