Yang Jie, Wang Shih-Kai, Choi Murim, Reid Bryan M, Hu Yuanyuan, Lee Yuan-Ling, Herzog Curtis R, Kim-Berman Hera, Lee Moses, Benke Paul J, Lloyd K C Kent, Simmer James P, Hu Jan C-C
Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University 22 South Avenue Zhongguancun Haidian District, Beijing, 100081, China ; Department of Biologic and Materials Sciences, University of Michigan School of Dentistry 1210 Eisenhower Place, Ann Arbor, Michigan, 48108.
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry 1210 Eisenhower Place, Ann Arbor, Michigan, 48108.
Mol Genet Genomic Med. 2015 Jan;3(1):40-58. doi: 10.1002/mgg3.111. Epub 2014 Sep 15.
WNT10A is a signaling molecule involved in tooth development, and WNT10A defects are associated with tooth agenesis. We characterized Wnt10a null mice generated by the knockout mouse project (KOMP) and six families with WNT10A mutations, including a novel p.Arg104Cys defect, in the absence of EDA,EDAR, or EDARADD variations. Wnt10a null mice exhibited supernumerary mandibular fourth molars, and smaller molars with abnormal cusp patterning and root taurodontism. Wnt10a (-/-) incisors showed distinctive apical-lingual wedge-shaped defects. These findings spurred us to closely examine the dental phenotypes of our WNT10A families. WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. Individuals with two defective WNT10A alleles showed severe tooth agenesis and had fewer cusps on their molars. The misshapened molar crowns and roots were consistent with the Wnt10a null phenotype and were not previously associated with WNT10A defects. The missing teeth contrasted with the presence of supplemental teeth in the Wnt10a null mice and demonstrated mammalian species differences in the roles of Wnt signaling in early tooth development. We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles.
WNT10A是一种参与牙齿发育的信号分子，WNT10A缺陷与牙齿发育不全有关。我们对由基因敲除小鼠项目（KOMP）产生的Wnt10a基因敲除小鼠以及六个有WNT10A突变的家系进行了特征分析，这些家系不存在EDA、EDAR或EDARADD变异，其中包括一种新的p.Arg104Cys缺陷。Wnt10a基因敲除小鼠表现出额外的下颌第四磨牙，以及较小的磨牙，伴有异常的牙尖形态和根融合牙。Wnt10a（-/-）小鼠的切牙表现出独特的根尖-舌侧楔形缺陷。这些发现促使我们仔细研究我们的WNT10A家系的牙齿表型。WNT10A杂合子在其恒牙列中表现出磨牙根融合牙和轻度牙齿发育不全（外显率不完全）。具有两个缺陷WNT10A等位基因的个体表现出严重的牙齿发育不全，磨牙上的牙尖较少。畸形的磨牙冠和牙根与Wnt10a基因敲除表型一致，且以前未与WNT10A缺陷相关联。缺失的牙齿与Wnt10a基因敲除小鼠中额外牙齿的存在形成对比，并证明了Wnt信号在早期牙齿发育中的作用存在哺乳动物物种差异。我们得出结论，磨牙冠和根的畸形是由WNT10A缺陷引起的，牙齿发育不全的严重程度与缺陷WNT10A等位基因的数量相关。
