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

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

doi:10.1016/j.jgg.2023.09.009

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

doi: 10.1016/j.jgg.2023.09.009

a 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;
b Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China;
c Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA;
d MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China;
e Department of Assisted Reproduction, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China;
f Children's Hospital, Fudan University, 399 Wanyuan Road, Shanghai 201102, China

Funds:

This work was 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, 82150008 to H.W., and 31000542 to X.Y.), and the Commission of Science and Technology of Shanghai Municipality (20JC1418500 to H.W.).

Received Date: 2023-03-05
Revised Date: 2023-09-14
Accepted Date: 2023-09-16

Available Online: 2023-09-24

Abstract

Abstract

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 four 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. The heterozygous Q199R mice show subtle kinked or shortened tails, while the 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 new evidence supporting the function of T in the genetic etiology of human CVM.
- congenital vertebral malformation,
- TBXT,
- T gene,
- loss-of-function mutation

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References(35)

References

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