A mutation in TBXT causes congenital vertebral malformations in humans and mice  

作　　者：Shuxia Chen Yunping Lei Yajun Yang Chennan Liu Lele Kuang Li Jin Richard HFinnell Xueyan Yang Hongyan Wang 

机构地区：[1]Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering at School of Life Sciences,Key Laboratory of Reproduction Regulation of NPFPC,Institute of Reproduction and Development,Fudan University,Shanghai 200438,China [2]Shanghai Key Laboratory of Metabolic Remodeling and Health,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200438,China [3]Center for Precision Environmental Health,Department of Molecular and Cellular Biology,Baylor College of Medicine,Houston,TX 77030,USA [4]MOE Key Laboratory of Contemporary Anthropology,School of Life Sciences,Fudan University,Shanghai 200438,China [5]Department of Assisted Reproduction,Xinhua Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200092,China [6]Children’s Hospital,Fudan University,399 Wanyuan Road,Shanghai 201102,China

出　　处：《Journal of Genetics and Genomics》2024年第4期433-442,共10页遗传学报（英文版）

基　　金：supported by the National Key R&D Program of China(2021YFC2701101 to H.W.and X.Y.);the National Natural Science Foundation of China(81930036 and 82150008 to H.W.,and 31000542 to X.Y.);the Commission of Science and Technology of Shanghai Municipality(20JC1418500 to H.W.).

摘　　要：T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.

关 键 词：Congenital vertebral malformation TBXT T gene Loss-of-function mutation 

分 类 号：R764.431[医药卫生—耳鼻咽喉科] R764.73[医药卫生—临床医学]