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Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein.

Böhm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U - BMC Med. Genet. (2008)

Bottom Line: Most of the TBX5 mutations found in patients with HOS cause premature truncation of the primary TBX5 transcript.In this study we present our functional analyses of the novel and unusual c.1333delC mutation found in a patient with classical HOS.The c.1333delC mutation affects neither the nuclear localization, nor its colocalization with SALL4, but severely affects the activation of the ANF promoter.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany. Johann.Boehm@titus.u-strasbg.fr

ABSTRACT

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.

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Related in: MedlinePlus

The patient. The patient presents bilateral hypoplastic clavicles and radii (A and C) and bilateral triphalangeal thumbs (B). Bradycardia due to atrioventricular block necessitates a pacemaker.
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Figure 1: The patient. The patient presents bilateral hypoplastic clavicles and radii (A and C) and bilateral triphalangeal thumbs (B). Bradycardia due to atrioventricular block necessitates a pacemaker.

Mentions: The now 4-year old male patient (Fig. 1) presented with typical manifestations of Holt-Oram syndrome: bilateral hypoplastic clavicles and radii (Fig. 1A, 1C), bilateral triphalangeal thumbs (Fig. 1B), total ASD and muscular VSD, bradycardia due to atrioventricular block requiring pacemaker, hypoplastic lung and pulmonary veins on the right side. He also had micrognathia and a long philtrum. Mental development is normal up to now.


Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein.

Böhm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U - BMC Med. Genet. (2008)

The patient. The patient presents bilateral hypoplastic clavicles and radii (A and C) and bilateral triphalangeal thumbs (B). Bradycardia due to atrioventricular block necessitates a pacemaker.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2567295&req=5

Figure 1: The patient. The patient presents bilateral hypoplastic clavicles and radii (A and C) and bilateral triphalangeal thumbs (B). Bradycardia due to atrioventricular block necessitates a pacemaker.
Mentions: The now 4-year old male patient (Fig. 1) presented with typical manifestations of Holt-Oram syndrome: bilateral hypoplastic clavicles and radii (Fig. 1A, 1C), bilateral triphalangeal thumbs (Fig. 1B), total ASD and muscular VSD, bradycardia due to atrioventricular block requiring pacemaker, hypoplastic lung and pulmonary veins on the right side. He also had micrognathia and a long philtrum. Mental development is normal up to now.

Bottom Line: Most of the TBX5 mutations found in patients with HOS cause premature truncation of the primary TBX5 transcript.In this study we present our functional analyses of the novel and unusual c.1333delC mutation found in a patient with classical HOS.The c.1333delC mutation affects neither the nuclear localization, nor its colocalization with SALL4, but severely affects the activation of the ANF promoter.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany. Johann.Boehm@titus.u-strasbg.fr

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus