PDF(Pubmed)
Abstract：
KCTD1 plays crucial roles in regulating both the SHH and WNT/β-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein-protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on β-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.
摘要：
KCTD1在调节SHH和WNT/β-catenin信号通路中起关键作用，对牙齿发育至关重要。这项研究的目的是调查KCTD1的遗传变异是否也可能与孤立的牙齿异常有关。我们在临床和影像学上调查了362例患有孤立性牙齿异常的患者。全外显子组测序确定了两个不相关的稀有家族（p。Arg241Gln）或新颖（p。Pro243Ser）在KCTD1中的变体。这两个家庭的所有9名患者的变体与牙齿异常隔离。患者的临床发现包括牛酮症，未分离的根,长根,牙齿发育不全,一颗多余的牙齿，TorusPalatinus,和下颌环面。Kctd1在根发育中的作用得到了我们的免疫组织化学研究的支持，该研究显示Kctd1在Hertwig上皮根鞘中的高表达。我们患者的KCTD1变体是发现位于C末端结构域的第一个变体，这可能会破坏蛋白质-蛋白质相互作用和/或SUMO化，并随后导致异常的WNT-SHH-BMP信号传导和孤立的牙齿异常。对p.Arg241Gln变体的功能研究与对β-连环蛋白水平和典型WNT信号传导的影响一致。这是有关KCTD1变体与孤立的牙齿异常关联的第一份报告。
