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Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation.

Abstract
Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD.
AuthorsAnwar Baban, Letizia Pitto, Silvia Pulignani, Monica Cresci, Laura Mariani, Carolina Gambacciani, Maria Cristina Digilio, Giacomo Pongiglione, Sonia Albanese
JournalAmerican journal of medical genetics. Part A (Am J Med Genet A) Vol. 164A Issue 6 Pg. 1419-24 (Jun 2014) ISSN: 1552-4833 [Electronic] United States
PMID24664498 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 Wiley Periodicals, Inc.
Chemical References
  • T-Box Domain Proteins
  • T-box transcription factor 5
Topics
  • Abnormalities, Multiple (genetics)
  • Aortic Coarctation (genetics)
  • Base Sequence
  • Brachydactyly (genetics)
  • Child
  • Endocardial Cushion Defects (genetics)
  • Heart Defects, Congenital (genetics)
  • Heart Septal Defects
  • Heart Septal Defects, Atrial (genetics)
  • Humans
  • Lower Extremity Deformities, Congenital (genetics)
  • Male
  • Mutation
  • Radius (abnormalities)
  • Sequence Analysis, DNA
  • Synostosis (genetics)
  • T-Box Domain Proteins (genetics)
  • Ulna (abnormalities)
  • Upper Extremity Deformities, Congenital (genetics)

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