Research article
Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein
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* Corresponding author: Jürgen Kohlhase jkohlhase@humangenetik-freiburg.de
- † Equal contributors
1 Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany
2 Institut für Humangenetik, Medizinische Fakultät der Universität Leipzig, Leipzig, Germany
3 Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden
4 Pediatric and Adolescent Medical Care, Skaraborg Hospital, Skovde, Sweden
5 Praxis für Humangenetik, Freiburg, Germany
BMC Medical Genetics 2008, 9:88 doi:10.1186/1471-2350-9-88
Published: 1 October 2008Abstract
Background
Autosomal dominant Holt-Oram syndrome (HOS) is caused by mutations in the TBX5 gene and is characterized by congenital heart and preaxial radial ray upper limb defects. Most of the TBX5 mutations found in patients with HOS cause premature truncation of the primary TBX5 transcript. TBX5 missense mutations alter the three-dimensional structure of the protein and result in failed nuclear localization or reduced binding to target DNA. In this study we present our functional analyses of the novel and unusual c.1333delC mutation found in a patient with classical HOS.
Methods
The functional impact of this novel mutation was assessed by investigating the intracellular localization of the resulting TBX5 protein and its ability to activate the expression of its downstream target ANF.
Results
The deletion of the cytosine is the first TBX5 frameshift mutation predicted to result in an elongated TBX5 protein with 74 miscoding amino acids and 62 supernumerary C-terminal amino acids. The c.1333delC mutation affects neither the nuclear localization, nor its colocalization with SALL4, but severely affects the activation of the ANF promoter.
Conclusion
The mutation c.1333delC does not locate within functional domains, but impairs the activation of the downstream target. This suggests that misfolding of the protein prevents its biological function.