A mutation in <i>TBXT</i> 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

Volume 51 Issue 4

Apr. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(4): 433-442

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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:

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.), and the Commission of Science and Technology of Shanghai Municipality (20JC1418500 to H.W.).

We sincerely appreciate the cooperation of the CVM-affected individuals and their families. We thank Dr. Yingzi Yang from the NIH for her support in generating the mouse model. We thank Dr. Hexige Saiyin for instruction in the pathological sections and immunofluorescence, and graduate student Xiangnan Li for statistical analyses of the microarray data, both from Fudan University.This work was supported by the National Key R&

Received Date: 2023-03-05
Accepted Date: 2023-09-16
Rev Recd Date: 2023-09-14
Publish Date: 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 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 malformation,
- TBXT,
- T gene,
- Loss-of-function mutation

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References(35)

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