Bruneau et al. (2001) generated heterozygous Tbx5 -/+ mice to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5 -/-) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (Anf, or Nppa) and connexin-40 (Cx40; 121013) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors causes disease. Direct and cooperative transactivation of the Anf and Cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provided a potential explanation for Holt-Oram syndrome conduction system defects, suggested mechanisms for intrafamilial phenotypic variability, and accounted for related cardiac malformations caused by other transcription factor mutations. In a Czech mother and 2 daughters diagnosed with Holt-Oram syndrome, Borozdin et al. (2006) identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency. In twin brothers and their father with ulnar-mammary syndrome, Tanteles et al. (2017) identified heterozygosity for a nonsense mutation in the TBX3 gene ( 601621.0006). Murakami et al. (2005) found that TAZ (WWTR1; 300394) was a potent TBX5 transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; 602700) and PCAF (602303). YAP (606608), a TAZ-related protein, also stimulated TBX5-dependent transcription. TBX5 with HOS-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ. Novel TBX3 mutation data in families with ulnar-mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects.

A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.

Funding

Koshiba-Takeuchi, K., Takeuchi, J. K., Matsumoto, K., Momose, T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H., Yasuda, K., Ogura, T. They receive free parking between the hours of 7.30pm and 8.00am while visiting the child. This would apply to a maximum of 2 vehicles. Parking will be provided free to all outpatients who attend hospital for an appointment at least 3 times within a month and for an overall period of at least 3 months. A ‘month’ is defined as a period of 30 days. Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Using SSCP analysis and direct sequencing of amplified products, Li et al. (1997) showed that the TBX5 gene was mutated in cases of familial and sporadic Holt-Oram syndrome (HOS; 142900) (see, e.g., 601620.0001).

Lenz (1968) noted that the involvement of the arms in the Holt-Oram syndrome can be sufficiently severe to simulate thalidomide embryopathy.

Companion Products

Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-mammary syndromes. To understand better the role of TBX5 in forelimb and heart development, Basson et al. (1999) studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations produced distinct phenotypes: gly80-to-arg ( 601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas arg237-to-gln ( 601620.0003) and arg237-to-trp ( 601620.0005) caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the 3-dimensional structure of a related T-box transcription factor, Xbra (of X. laevis), bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggested that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences. Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. Bamshad et al. (1999) identified novel mutations in the TBX3 gene in all of 8 newly reported families with UMS, including 5 mutations downstream of the region encoding the T-box. This suggested that a domain (or domains) outside the T-box was highly conserved and important for the function of TBX3. Bamshad et al. (1999) found no obvious phenotypic differences between those who had missense mutations and those who had deletions or frameshifts.