Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

A novel mutated sequence in the T-box transcription factor-5 (TBX-5) gene (c.241A>T) in Holt–Oram syndrome

“…The clinical implications of TBX5 missense mutations, which are less frequently seen, are not clearly known, but it was denoted that these mutations seem to result in lesser severe cases than other types of mutations, predominantly cardiac or skeletal deformities (5,8). In a recent review by Al-Qattan and Abou Al-Shaar, the clinical heterogeneity of HOS was well established.…”

“…In a recent review by Al-Qattan and Abou Al-Shaar, the clinical heterogeneity of HOS was well established. They highlighted that there were three different mutation groups in TBX5 gene: the first one was a single base change, e.g., missense mutations, causing a specific amino acid deficiency with regard to change in the associated nucleotide; second mutation caused extended protein changes; and third was the intragenic duplication of a region (8). A missense mutation altering an amino acid near the amino-terminal end of the T-box causes more considerable cardiac malformations, while a different missense mutation near the carboxyl end causes predominantly more severe upper limb deformities (frequently left-sided deformity) (5).…”

“…Extended protein mutations are more inclined to cause severe bilateral skeletal malformations and more severe cardiac anomalies. Intragenic duplications have been reported to entail more severe cardiac anomalies rather than severe skeletal anomalies (8). In a recent case report by Kimura et al (9), duplication screening was offered for families that had unidentified genetic structure.…”

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

“…Remarkably, approximately 70% of patients who are diagnosed with HOS exhibit a mutation in the TBX5 gene (55). To date, numerous HOS-related mutations of the TBX5 gene have been reported in humans (56). Recently, a new mutation in the DNA binding domain of TBX5 (p.Pro85Thr) that leads to a conformational change in protein structure has been described by our group (57).…”

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

“…mice mimic heart and limb abnormalities observed in Holt-Oram (''heart-hand'') syndrome (HOS) in humans [36]. Of note, TBX5 was the first T-box gene where loss-of-function mutations (mainly located within the highly conserved T-box domain) were found to cause a HOS (recently reviewed in [37]); diastolic dysfunction is detected in a cohort of HOS patients [38]. Patients with low diastolic blood pressure show substantially increased ventricular-arterial stiffness and a tendency for diastolic dysfunction (reviewed in [39]).…”