Expressivity of Holt-Oram Syndrome Is Not Predicted by TBX5 Genotype

Abstract

Mutations in TBX5, a T-box-containing transcription factor, cause cardiac and limb malformations in individuals with Holt-Oram syndrome (HOS). Mutations that result in haploinsufficiency of TBX5 are purported to cause cardiac and limb defects of similar severity, whereas missense mutations, depending on their location in the T box, are thought to cause either more severe heart or more severe limb abnormalities. These inferences are, however, based on the analysis of a relatively small number of independent cases of HOS. To better understand the relationship between mutations in TBX5 and the variable expressivity of HOS, we screened the coding and noncoding regions of TBX5 and SALL4 for mutations in 55 probands with HOS. Seventeen mutations, including six missense mutations in TBX5 and two mutations in SALL4, were found in 19 kindreds with HOS. Fewer than 50% of individuals with nonsense or frameshift mutations in TBX5 had heart and limb defects of similar severity, and only 2 of 20 individuals had heart or limb malformations of the severity predicted by the location of their mutations in the T box. These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

“…The decrease in gene expression induction suggests that the developmental defects in HOS could be caused by insufficiency of the expression of Tbx5-induced genes, including nppa, CKB, prCAD, and hey2. Although conflicting reports exist regarding whether the severity of the HOS phenotype can be correlated with a specific mutation, our data suggest that the R237Q mutation, and the R279ter mutation vary in their ability to disrupt Tbx5 transcriptional function affecting multiple target genes (Basson et al, 1999;Brassington et al, 2003). Consequently, distinct phenotypes resulting from either mutation may occur because expression of the transcriptional targets of Tbx5 is variably affected.…”

The human TBX5 gene mutation database

“…Nevertheless, it was shown, that the amino acid residues 1 to 54 and 238 to 518, which are not fully conserved over various species, are also required for effective DNA-binding and gene function (Ghosh et al, 2001). This was confirmed by the identification of different mutations in the N-and C-terminal part of the TBX5 gene in patients with Holt-Oram syndrome, which are presumably essential for a correct function of TBX5 (Li et al, 1997;Cross et al, 2000;Yang et al 2000;Brassington et al, 2003;Heinritz et al, 2005 …”

“…Functional impairment due to mutations within the gene appears to cause not only HOS, but also complex congenital heart malformations in Non-HOS individuals. To date 41 different germline mutations were described in the TBX5 gene on the DNA level in families or sporadic cases with Holt-Oram syndrome (Basson et al, 1997(Basson et al, , 1999Li et al, 1997;Cross et al, 2000;Yang et al, 2000;Brassington et al, 2003;Fan et al, 2003;Gruenauer-Kloevekorn and Froster, 2003;Heinritz et al, 2005). Furthermore, 9 different somatic mutations were reported in diseased heart tissues of patients with non-HOS related con-DOI: 10.1002/humu.9375 genital heart defects (Reamon- Buettner and Borlak, 2004).…”

A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt–Oram syndrome

“…In many cases, haploinsufficiency of T-box genes results in dramatic morphological abnormalities, emphasizing the importance of specific thresholds of transcriptional activity of T-box factors for developmental decisions (4). For example, heterozygous mutations in TBX1 have been implicated in 22q11 deletion (DiGeorge) syndrome, characterized by abnormalities in the aortic arch arteries due to defects in neural crest cell migration (4,6), and mutations in TBX5 cause Holt-Oram syndrome (HOS), which manifests as a variety of cardiac and upper limb abnormalities (7)(8)(9)(10)(11).…”