![]() ![]() The function of tbx5 in the heart appears to be exquisitely sensitive to gene dosage, since either haploinsufficiency or gene duplication can produce the cardiac abnormalities associated with Holt-Oram syndrome ( Dixon et al., 1993 Hatcher and Basson, 2001 McCorquodale et al., 1986 Melnyk et al., 1981). Mutations in TBX1 are responsible for the DiGeorge syndrome ( Lindsay et al., 2001 Merscher et al., 2001). Mutations in TBX22 cause the rare syndrome CPX (X-linked cleft palate and tongue-tie) ( Braybrook et al., 2001). TBX3 mutations produce ulnar-mammary syndrome ( Bamshad et al., 1997 Bamshad et al., 1999). For example, mutations in TBX5 cause human Holt-Oram syndrome, characterized by congenital defects in the heart and upper limbs ( Basson et al., 1997 Li et al., 1997). T-box genes play key roles in cell-type specification and morphogenesis ( Smith, 1999), and mutations in several T-box genes have been shown to result in human developmental disorders ( Murray, 2001). T-box genes are represented throughout metazoan evolution, and vertebrates alone include over 20 family members ( Tada and Smith, 2001). Members of the T-box family of transcription factors contain a highly conserved DNA binding motif of 180-190 amino acid residues ( Murray, 2001 Simon, 1999 Tada and Smith, 2001). However, the syndromic deficiencies of tbx5 mutation are remarkably well retained between fish and mammals. Relative to mammals, fish require lower levels of Tbx5 to produce malformed appendages and display whole-heart rather than atrial-predominant cardiac defects. However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. The heart of heartstrings mutant embryos appears to form and function normally through the early heart tube stage, manifesting only a slight bradycardia compared with wild-type siblings. Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. ![]() The total absence of any fin bud differentiation distinguishes heartstrings from most other mutations that affect zebrafish fin development, suggesting that Tbx5 functions very early in the pectoral fin induction pathway. Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. The heartstrings mutation causes premature termination at amino acid 316. We mapped and cloned the heartstrings mutation and find it to encode the zebrafish ortholog of the TBX5 gene. In a screen for mutations affecting zebrafish cardiac function, we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction, beginning with a slow heart rate and progressing to a stretched, non-functional heart. ![]() Holt-Oram syndrome is caused by mutations in the TBX5 gene, a member of a large family of T-box transcription factors that play important roles in cell-type specification and morphogenesis. Holt-Oram syndrome is one of the autosomal dominant human ‘heart-hand’ disorders, with a combination of upper limb malformations and cardiac defects.
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