Language
English
Publication Date
4-1-2024
Journal
Journal of Genetics and Genomics
DOI
10.1016/j.jgg.2023.09.009
PMID
37751845
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.
Keywords
Humans, Mice, Animals, Spine, Mutation, Genotype, Heterozygote, Phenotype, Congenital vertebral malformation, Loss-of-function mutation, T gene, TBXT
Published Open-Access
yes
Recommended Citation
Chen, Shuxia; Lei, Yunping; Yang, Yajun; et al., "A Mutation in Tbxt Causes Congenital Vertebral Malformations in Humans and Mice" (2024). Faculty and Staff Publications. 4857.
https://digitalcommons.library.tmc.edu/baylor_docs/4857
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons