Disease relevance of TBX5

• Seven missense mutations in TBX5 have been identified in patients with Holt-Oram syndrome characterized by congenital heart defects and upper limb abnormalities [1].
• Mutations in TBX5 have already been shown to cause similar atrial septal defects in Holt-Oram syndrome [2].
• TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro [3].
• The TBX5 gene, which encodes another cardiac transcription factor that collaborates with NKX2.5, is also an important cardiac disease gene, with heterozygous mutations responsible for Holt-Oram (hand/heart) syndrome [4].
• 2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome [5].

High impact information on TBX5

• Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc-finger transcription factor, cause similar upper limb and heart defects [6].
• Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome [7].
• Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation [8].
• Deletion analysis showed that both the N-terminal domain and T-box of Tbx5 were important for this transactivation [8].
• A G80R mutation of Tbx5, which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not activate Nppa or show synergistic activation, whereas R237Q, which causes upper-limb malformations without cardiac abnormalities, activated the Nppa promoter to a similar extent to that of wildtype Tbx5 [8].

Biological context of TBX5

• In this study we describe functional defects in DNA binding, transcriptional activity, protein-protein interaction, and cellular localization of mutant TBX5 with these missense mutations (Q49K, I54T, G80R, G169R, R237Q, R237W, and S252I) [1].
• 5. The second group of mutations includes Q49K, I54T, G169R, and S252I, which have no or moderate effect on DNA-binding activity and the function of transcription activation of TBX5 but cause the complete loss of synergistic transcription activity between TBX5 and NKX2 [1].
• TBX5 is a T-box transcription factor that plays a critical role in organogenesis [1].
• Partial dysfunction of TBX5 in mouse also causes HOS phenotype [9].
• Here, we report that ectopic expression of TBX5 inhibited colony formation, induced apoptosis, and decreased the growth rate of cells [9].

Anatomical context of TBX5

• In embryonic and adult heart, TBX5 is expressed throughout the epicardium and in cardiomyocyte nuclei in myocardium of all four cardiac chambers [10].
• Endocardial expression of TBX5 is only present in left ventricle [10].
• P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutant did not differentiate into beating cardiomyocytes [8].
• Co-transfection of Nkx2-5 and Tbx5 into COS-7 cells showed that they also associate with each other in mammalian cells [8].
• Blocking cell cycle progression by TBX5 depletion leads to a decrease in cardiac cell number, an alteration in the timing of the cardiac differentiation program, defects in cardiac sarcomere formation, and ultimately, to cardiac programmed cell death [11].

Other interactions of TBX5

• CONCLUSIONS: The expression pattern of TBX2, TBX3, and TBX5 within the developing retina supports the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping and in differentiation of distinct cell types across the laminar axis of the retina [12].
• GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 [13].
• 5. All seven missense mutations greatly reduced the interaction of TBX5 with NKX2.5 in vivo and in vitro [1].
• Specifically, there is overlap of clinical features with other conditions, most notably Holt-Oram syndrome, a condition resulting from mutation of the TBX5 locus and Townes-Brocks syndrome, known to be caused by mutations in the SALL1 gene [14].
• Thus, it is thought that Tbx5 and Tbx4 might be involved in determining limb identity [15].

Analytical, diagnostic and therapeutic context of TBX5

• Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development [16].
• To determine the biochemical mechanisms underlying TBX5 nuclear import, we performed site-directed mutagenesis of human TBX5 [17].
• Sequence analysis identified three novel, heterozygous mutations in TBX5: a frameshift mutation caused by one base deletion [C416del] in one family, a mis-sense mutation (Gln49Lys) induced by a base substitution (C145A) in another family, and the other mis-sense mutation (Ile54Thr) by T161C in one sporadic case [18].
• We developed a quantitative Real Time PCR strategy to detect large, submicroscopic deletions in TBX5 [19].
• The expression profile of TBX5 in rat tissues was studied by RT-PCR and Northern blot [20].

References