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: Congenital vertebral malformation; Loss-of-function mutation; T gene; TBXT.
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