A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function

Dreßen, Martina and Lahm, Harald and Lahm, Armin and Wolf, Klaudia and Doppler, Stefanie and Deutsch, Marcus-André and Cleuziou, Julie and Pabst von Ohain, Jelena and Schön, Patric and Ewert, Peter and Malčić, Ivan and Lange, Rüdiger and Krane, Markus (2016) A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function. Molecular Genetics & Genomic Medicine, 4 (5). pp. 557-567. ISSN 2324-9269

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Abstract

BACKGROUND: The Holt-Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15-month-old patient being investigated for strict diagnostic criteria of HOS. ----- METHODS AND RESULTS: Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T-box transcription factors playing major roles in morphogenesis and cell-type specification. The mutation located in the DNA-binding domain at position 920 (C→A) leads to an amino acid change at position 85 (proline → threonine). Three-dimensional analysis of the protein structure predicted a cis to trans change in the respective peptide bond, thereby probably provoking major conformational and functional alterations of the protein. The p.Pro85Thr mutation showed a dramatically reduced activation (97%) of the NPPA promoter in luciferase assays and failed to induce NPPA expression in HEK 293 cells compared to wild-type TBX5 protein. The mutation did not interfere with the nuclear localization of the protein. ----- CONCLUSION: These results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient.

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