Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart. The Tbx5 gene is a transcription factor that codes for the protein called T-box 5. Along with playing roles in the development of the heart, septum, and electrical system of the heart, it also activates genes that are involved in the development of the upper limbs, the arms and hands. This gene is involved in patterning major aspects of the heart; however, it is also involved in the muscle connective tissue for muscle and tendon patterning. A study showed that deletion of Tbx5 in forelimbs causes disruption in the muscle and tendon patterning without affecting the skeletons development. Tbx5 expression is in the cells of the lateral plate mesoderm which form the forelimb bud and the cascade of limb initiation. In its absence no forelimb bud forms. Diseases and defects associated with this gene are Holt-Oram syndrome, both have to do with limb defects and several other abnormalities. The cardiac defects include defects in the septum dividing the left and right sides of the heart, conduction system abnormalities, and other problems. The exact mechanism that Tbx5 activates gene expression is still being discovered and is actively being understood.
Clinical significance
The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system. Several transcript variants encoding different isoforms have been described for this gene. In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past embryonic day E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome. Supporting the essential role of TBX5 in the heart development. The encoded protein plays a major role in limb development, specifically during limb bud initiation. For instance, in chickens Tbx5 specifies forelimb status. The activation of Tbx5 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds. Ultimately, Tbx5 leads to the development of apical ectodermal ridge and zone of polarizing activity signaling centers in the developing limb bud, which specify the orientation growth of the developing limb. Together with Tbx4, Tbx5 plays a role in patterning the soft tissues of the musculoskeletal system. A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome. Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum. Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms. An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias. Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations. This condition can lead to the absence of one or both forelimbs.
