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

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

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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 malfor-mations(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.

Congenital vertebral malformationTBXTT geneLoss-of-function mutation

Shuxia Chen、Yunping Lei、Yajun Yang、Chennan Liu、Lele Kuang、Li Jin、Richard H.Finnell、Xueyan Yang、Hongyan Wang

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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

Shanghai Key Laboratory of Metabolic Remodeling and Health,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200438,China

Center for Precision Environmental Health,Department of Molecular and Cellular Biology,Baylor College of Medicine,Houston,TX 77030,USA

MOE Key Laboratory of Contemporary Anthropology,School of Life Sciences,Fudan University,Shanghai 200438,China

Department of Assisted Reproduction,Xinhua Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200092,China

Children's Hospital,Fudan University,399 Wanyuan Road,Shanghai 201102,China

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National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaCommission of Science and Technology of Shanghai Municipality

2021YFC270110181930036821500083100054220JC1418500

2024

10.1016/j.jgg.2023.09.009

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(4)
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