Abstract：
BACKGROUND: Low density lipoprotein receptor-related protein 4 (LRP4; MIM 604270) modulates WNT/β-catenin signaling, through its binding of WNT ligands, and to co-receptors LRP5/6, and WNT inhibitors DKK1, SOSTDC1, and SOST. LRP4 binds to SOSTDC1 and WNT proteins establishing a negative feedback loop between Wnt/β-catenin, Bmp, and Shh signaling during the bud and cap stages of tooth development. Consistent with a critical role for this complex in developing teeth, mice lacking Lrp4 or Sostdc1 have multiple dental anomalies including supernumerary incisors and molars. However, there is limited evidence supporting variants in LRP4 in human dental pathologies.
METHODS: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice.
RESULTS: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice.
CONCLUSIONS: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/β-catenin-BMP-SHH signaling.
METHODS: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice.
RESULTS: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice.
CONCLUSIONS: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/β-catenin-BMP-SHH signaling.
摘要：
背景：低密度脂蛋白受体相关蛋白4（LRP4;MIM604270）调节WNT/β-catenin信号传导，通过它与WNT配体的结合，以及共受体LRP5/6和WNT抑制剂DKK1、SOSTDC1和SOST。LRP4与SOSTDC1和WNT蛋白结合，在Wnt/β-catenin之间建立负反馈环，BMP,和Shh信号在牙齿发育的芽和帽阶段。与这种复合体在牙齿发育中的关键作用一致，缺乏Lrp4或Sostdc1的小鼠有多个牙齿异常，包括多余的门牙和磨牙。然而,在人类牙病中支持LRP4变异的证据有限.
方法：我们在临床上，射线照相，并对94名泰国患者进行了分子调查。产生Lrp4突变小鼠以研究小鼠中异常Lrp4表达的影响。
结果：全外显子组和Sanger测序确定了三种极其罕见的变异（c.4151A>G，p.Asn1385Ser;c.3940G>A,p.Gly1314Ser;和c.448G>A，p.Asp150Asn）在7例患者的LRP4中。两名患者患有口腔外生骨，两名患者患有根部发育不良。在Lrp4突变小鼠中观察到了多余的切牙。
结论：我们的研究提示LRP4中的杂合遗传变异是mesiodens呈递的促成因素，根发育不良，和口腔外生骨，可能是WNT/β-连环蛋白-BMP-SHH信号传导改变的结果。
方法：我们在临床上，
结果：全外显子组和Sanger测序确定了三种极其罕见的变异（c.4151A>G，
结论：我们的研究提示LRP4中的杂合遗传变异是mesiodens呈递的促成因素，
