Xiong Fu, Ji Zhisong, Liu Yanhui, Zhang Yu, Hu Lingling, Yang Qi, Qiu Qinwei, Zhao Lingfeng, Chen Dong, Tian Zhihui, Shang Xuan, Zhang Leitao, Wei Xiaofeng, Liu Cuixian, Yu Qiuxia, Zhang Meichao, Cheng Jing, Xiong Jun, Li Dongri, Wu Xiuhua, Yuan Huijun, Zhang Wenqing, Xu Xiangmin
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Prenatal Diagnosis Center, Maternal and Child Health Hospital, Dongguan, China.
Hum Mutat. 2017 Jan;38(1):95-104. doi: 10.1002/humu.23130. Epub 2016 Oct 19.
Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.
I型牙本质发育异常（DDI）是一种由牙本质缺陷导致的常染色体显性遗传病。DDI的分子基础尚不清楚。DDI具有独特的特征，其表型包括髓腔闭塞和牙根短小，因此为理解牙齿形成的遗传学提供了一个有用的模型。我们对一个有14名DDI患者的中国大家庭进行研究，将导致DDI的基因座定位到3p26.1 - 3p24.3，并进一步在3p26.1上的SSUH2基因中鉴定出一个错义突变c.353C>A（p.P118Q），该突变与DDI共分离。我们发现，与野生型SSUH2相比，SSUH2（p.P118Q）扰乱了结构，显著降低了突变体（MT）蛋白和mRNA的水平。此外，MT P141Q基因敲入小鼠（+/-和-/-）具有独特的牙髓腔部分闭塞以及六个参与牙发生的主要基因（Dspp、Dmp1、Runx2、Pax9、Bmp2和Dlx2）的上调或下调。通过吗啉代基因敲低在斑马鱼中确定了缺牙表型，并通过注射正常人mRNA得以挽救。综上所述，我们的观察结果表明，SSUH2破坏牙齿形成，并且这个新基因与其他牙发生基因一起参与牙齿发育。
