先天性牙发育不全WNT6基因突变的新位点  

A novel mutation in the WNT6 gene of congenital tooth agenesis

作　　者：戴卓 李丽丽[1] 张晓昕 牟永斌[1] 陈斌[1] DAI Zhuo;LI Lili;ZHANG Xiaoxin;MOU Yongbin;CHEN Bin(Nanjing Stomatological Hospital,Medical School of Nanjing University,Nanjing 210008,China)

机构地区：[1]南京大学医学院附属口腔医院,江苏南京210008

出　　处：《口腔疾病防治》2023年第8期552-558,共7页Journal of Prevention and Treatment for Stomatological Diseases

基　　金：国家自然科学基金(82002865);江苏省自然科学基金项目(BK20220199);江苏省重点研发计划(社会发展)项目(BE2020629)。

摘　　要：目的探讨先天性牙发育不全病例与相关基因突变可能存在的联系,为疾病的早期诊断提供参考。方法通过收集1例罕见先天性牙发育不全病例的临床和影像学资料,评估牙齿的形态、数量以及全身健康状况;采集患者静脉外周血,对与牙齿发育紧密关联的PAX9和MSX1基因双向测序;进行全外显子测序,筛查与牙发育异常相关的其他突变位点,对先证者儿子进行新发现突变位点的Sanger测序;通过模拟测算工具和体外细胞转染实验评估突变对基因表达的影响。结果患者的临床特征是先天性右下颌单侧第一磨牙缺失,第二磨牙为单根,且伴有右下第二前磨牙多生。在PAX9和MSX1基因测序中发现,PAX9基因中c.717C>C/T为同义突变,MSX1基因中c.119C>G为错义突变,Polyphen预测为“良性”。全外显子测序发现WNT6基因的1个全新突变位点,内含子3中的c.637-7 C>A突变,经MAXENT预测,可能影响mRNA的剪切,且先证者及其儿子均携带该突变;细胞转染实验发现,该突变对WNT6基因的mRNA剪切没有影响。结论单核苷酸多态性之间的相互作用可能与先天性牙发育异常相关。Objective This article explores the relationship between congenital tooth agenesis and related gene mu⁃tations,providing a reference for early diagnosis of the disease.Methods Clinical and radiographic examinations of a rare case of congenital tooth agenesis were conducted to evaluate the abnormal morphology and quantity of the teeth,as well as the overall health of the patient.Bidirectional sequencing of the PAX9 and MSX1 genes and whole⁃exome se⁃quencing were conducted to identify potential genetic abnormalities.Sanger sequencing of the newly discovered muta⁃tion site was performed on the proband's son.Subsequently,the impacts of the mutations were evaluated through compu⁃tational tools and a cell⁃based gene transfection assay.Results This is a rare case of tooth agenesis characterized by a congenitally missing first molar,a second molar with one single root and a supernumerary second premolar in the right mandibular dentition.The c.717 C>C/T in PAX9 is synonymous.The c.119C>G in MSX1 is a missense mutation pre⁃dicted to be“benign”by Polyphen.Through whole⁃exome sequencing,we found a novel mutation,c.637⁃7 C>A in in⁃tron 3 of the WNT6 gene,which is predicted by MAXENT to influence the splicing of mRNA.Both the proband and his son carry this mutation.A cell⁃based gene transfection assay demonstrated that it did not alter the mRNA splicing of WNT6.Conclusion The interaction between single nucleotide polymorphisms may contribute to congenital tooth agen⁃esis.

关 键 词：牙发育不全 非综合征型 剪切突变 全外显子测序 WNT6基因 PAX9基因 MSX1基因 单核苷酸多态性 

分 类 号：R78[医药卫生—口腔医学]