在KIF3C和ZNF513中发生的双重异构致病突变会导致遗传性牙纤维化
Jianfan Chen1,2, Xueqing Xu3, Song Chen1
1Department of Medical Genetics, Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
International journal of oral science
|September 26, 2023
概括
在ZNF513和KIF3C基因的双重突变导致遗传性牙纤维化 (HGF). 这项研究确定ZNF513和KIF3C是HGF发育的关键遗传因素,ZNF513突变是显著的风险因素.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 遗传性牙纤维化 (HGF) 是一种罕见的遗传性疾病,其特征是牙组织过度生长.
- 在HGF中存在遗传异质性,以前只有SOS1和REST被确定为引起疾病的基因.
- GINGF3位点与HGF有关,但其致病基因在很大程度上仍未知.
研究的目的:
- 在一个多个受影响个体的家庭中确定HGF的遗传基础.
- 阐明已识别的基因突变对HGF有所贡献的功能机制.
- 调查ZNF513和KIF3C在牙纤维化病中的联合作用.
主要方法:
- 一个26名成员的家庭的家谱分析,其中有9名高血压患者.
- 整体外基因组测序以识别致病突变.
- 在体外和体外功能测试以评估基因表达和蛋白质相互作用.
- 生成和分析Zfp513/Kif3c敲入鼠标模型.
主要成果:
- 在GINGF3位点内发现了ZNF513 (p.R250W) 和KIF3C (p.R410H) 的双重异构致病突变.
- 在ZNF513和KIF3C的突变增加了各自的基因表达,并影响了牙纤维细胞功能.
- 一种小鼠模拟模型显示,Zfp513和Kif3c突变的组合,而不是单个突变,导致牙增生表型.
- 发现ZNF513调节SOS1表达,而KIF3C突变激活PI3K和KCNQ1通道.
- 这种ZNF513-KIF3C相互作用会影响牙纤维细胞通路 (PI3K/AKT/mTOR,Ras/Raf/MEK/ERK).
结论:
- ZNF513和KIF3C协同作用,调节牙纤维细胞的增殖,迁移和纤维化,导致HGF.
- 已识别的ZNF513和KIF3C突变是对HGF的关键遗传贡献者.
- ZNF513突变可能是遗传性牙纤维化发展的重要危险因素.
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