Duplication of the 17q23.1–q23.2 region, which includes the Tbx4 gene, has been reported to result in congenital clubfoot. Tbx4 duplication within this region has been determined to be the gene that leads to this phenotype. TBX4 gene mutations lead to an autosomal-dominant disorder called small patella syndrome, also known as Scott-Taor syndrome, which is characterized by patellar aplasia and abnormalities of the pelvis and feet. Mutations in the TBX4 that cause small patella syndrome are also associated with childhood-onset pulmonary arterial hypertension. Deletion of 17q23.2 or a point mutation in the TBX4 gene is reported in 30% of patients with childhood-onset PAH, whereas TBX4 gene mutations are associated with low frequency in adult-onset PAH patients. Using targeted mutagenesis of Tbx4 in the mouse, various abnormalities were observed in the development of the allantois. Choirioallantoic fusion fails to occur in embryos with the homozygous null allele resulting in death 10.5 days post coitus, embryos with the Tbx4-mutant gene were observed to have allantoises that were apoptotic, stunted, and displayed abnormal differentiation with endothelial cells resulting in the absence of vascular remodeling.
Role
Tbx4 is a transcription factor and member of the T-box family, which have been shown to play important role in fetal development. Tbx4 is expressed in a wide variety of tissues during organogenesis, including the hindlimb, proctodeum, mandibular mesenchyme, lung mesenchyme, atrium of the heart and the body wall. Tbx4 is specifically expressed in the visceral mesoderm of the lung primordium and governs multiple processes during respiratory tract development such as initial endodermal bud development, respiratory endoderm formation, and septation of the respiratory tract and esophagus. Along with Tbx4, Tbx5 is also expressed to help with development of limbs. Tbx4 is expressed in the hindlimb, whereas Tbx5 is expressed in the forelimb, heart, and dorsal side of the retina. Studies have shown that fibroblast growth factor play a key role in limb initiation. In a developing embryo a gradient of retinoic acid aids in the combinatorial patterns of Hox gene expression along the body axis, which causes regions of the paraxial mesoderm to emit a signal to the lateral mesoderm that causes the expression of Tbx4 and Tbx5. When these two molecules are expressed that stimulate the secretion of FGF-10, which will induce the ectoderm to produce FGF-8. FGF-8 and FGF-10 together promote limb development. Mutations or teratogens that interfere with Tbx4/Tbx5 or FGF-8/FGF-10 has the ability to cause a child to be born without one or more limbs. A common syndrome seen with a mutation these genes is Tetra-Amelia syndrome which is characterized by the absence of all four limbs and anomalies involving the cranium and the face; eyes; urogenital system; heart; lungs and central nervous system. In a study done by Naiche et al. they generated a knockout mouse in which it lacked the expression on Tbx4 this mouse resulted in a phenotype of no limb formation.
