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Hum Mutat. 2004 Jul;24(1):104.

TBX5 mutations in non-Holt-Oram syndrome (HOS) malformed hearts.

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Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, D-30625 Hannover, Germany.


The T-box transcription factor Tbx5 is important in mammalian cardiac development. Mutations in the human TBX5 gene cause Holt-Oram syndrome (HOS), a disorder characterized by heart and upper limb deformities. To determine the role of TBX5 in non-HOS patients with complex cardiac malformations, we analyzed 68 explanted hearts from unrelated patients with various cardiac abnormalities including atrial (ASD), ventricular (VSD) and atrioventricular septal defects (AVSD). Direct sequencing detected nine mutations in diseased cardiac tissues of patients, eight of which are novel. Six mutations would affect amino acids in the T-domain, and one (c.236C>T, p.Ala79Val) is within the recently identified nuclear localization signal (NLS1) region. Further, mutations were found in patients with ASD and AVSD, but not with VSD; and mutations were absent in normal heart tissue of same patients, thus indicating somatic origin. Our results suggest a possible role of somatically occurring TBX5 mutations in congenital heart disease. We show for the first time TBX5 mutations in non-HOS associated cardiac malformations and we identified a novel missense mutation that would impact nuclear localization of TBX5.

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