title: A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function.
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.
  
  
  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  Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents.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.
  
  
  CONCLUSIONS
  These results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient.
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dreßen
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Lahm
authors.affiliation: Bioinformatics Project Support Rome Italy.
authors.forename: Armin
authors.initials: A
authors.lastname: Lahm
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Wolf
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Doppler
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Marcus-André
authors.initials: MA
authors.lastname: Deutsch
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Cleuziou
authors.affiliation: Department of Cardiovascular Surgery Division of Experimental Surgery German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Pabst von Ohain
authors.affiliation: Department of Paediatric Cardiology and Congenital Heart Defects German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Patric
authors.initials: P
authors.lastname: Schön
authors.affiliation: Department of Paediatric Cardiology and Congenital Heart Defects German Heart Center Munich at the Technical University of Munich Munich Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ewert
authors.affiliation: Department of Pediatrics Division of Cardiology and Intensive Care Unit University Hospital Zagreb Zagreb Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Malcic
authors.affiliation: Department of Cardiovascular SurgeryDivision of Experimental SurgeryGerman Heart Center Munich at the Technical University of MunichMunichGermany; DZHK (German Center for Cardiovascular Research) - partner site Munich Heart AllianceMunichGermany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Lange
authors.affiliation: Department of Cardiovascular SurgeryDivision of Experimental SurgeryGerman Heart Center Munich at the Technical University of MunichMunichGermany; DZHK (German Center for Cardiovascular Research) - partner site Munich Heart AllianceMunichGermany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krane
keywords: Congenital heart disease; Holt–Oram syndrome; TBX5; de novo mutation; heart‐hand syndrome; loss‐of function; transcription factor