Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand.
Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
Int J Paediatr Dent. 2024 Jul;34(4):432-441. doi: 10.1111/ipd.13141. Epub 2023 Nov 27.
In order to generate a normal set of teeth, fine-tuning of Wnt/β-catenin signaling is required, in which WNT ligands bind to their inhibitors or WNT inhibitors bind to their co-receptors. Lrp4 regulates the number of teeth and their morphology by modulating Wnt/β-catenin signaling as a Wnt/β-catenin activator or inhibitor, depending on its interactions with the partner proteins, such as Sostdc1 and Dkk1.
To investigate genetic etiologies of dental anomalies involving LRP4 in a Thai cohort of 250 children and adults with dental anomalies.
Oral and radiographic examinations and whole exome sequencing were performed for every patient.
Two novel (p.Leu1356Arg and p.Ala1702Gly) and three recurrent (p.Arg263His, p.Gly1314Ser, and p.Asn1385Ser) rare variants in low-density lipoprotein receptor-related protein 4 (LRP4: MIM 604270) were identified in 11 patients. Oral exostoses were observed in five patients.
Antagonism of Bmp signaling by Sostdc1 requires the presence of Lrp4. Mice lacking Lrp4 have been demonstrated to have alteration of Wnt-Bmp-Shh signaling and an abnormal number of incisors. Therefore, the LRP4 mutations found in our patients may disrupt Wnt-Bmp-Shh signaling, thereby resulting in dental anomalies and oral exostoses. Root maldevelopment in the patients suggests an important role of LRP4 in root morphogenesis.
为了生成正常的牙齿，需要对 Wnt/β-连环蛋白信号进行微调，其中 WNT 配体与它们的抑制剂结合或 WNT 抑制剂与它们的共受体结合。LRP4 通过作为 Wnt/β-连环蛋白激活剂或抑制剂来调节 Wnt/β-连环蛋白信号，从而调节牙齿的数量和形态，这取决于其与伴侣蛋白（如 Sostdc1 和 Dkk1）的相互作用。
在泰国的 250 名患有牙齿异常的儿童和成人的队列中，研究涉及 LRP4 的牙齿异常的遗传病因。
对每位患者进行口腔和影像学检查以及外显子组测序。
在 11 名患者中发现了两种新的（p.Leu1356Arg 和 p.Ala1702Gly）和三种复发性（p.Arg263His、p.Gly1314Ser 和 p.Asn1385Ser）低密脂蛋白受体相关蛋白 4（LRP4：MIM 604270）的罕见变异。五名患者观察到口腔外生骨瘤。
Sostdc1 通过 Bmp 信号的拮抗作用需要 Lrp4 的存在。缺乏 Lrp4 的小鼠已被证明具有 Wnt-Bmp-Shh 信号的改变和切牙数量异常。因此，我们患者中发现的 LRP4 突变可能破坏了 Wnt-Bmp-Shh 信号，从而导致牙齿异常和口腔外生骨瘤。患者的牙根发育不良表明 LRP4 在牙根形态发生中起着重要作用。
