HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function.

Abstract
TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons.
AuthorsAbir Yamak, Romain O Georges, Massomeh Sheikh-Hassani, Martin Morin, Hiba Komati, Mona Nemer
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 11 Pg. 6844-56 (Mar 13 2015) ISSN: 1083-351X [Electronic] United States
PMID25623069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Protein Isoforms
  • T-Box Domain Proteins
  • T-box transcription factor 5
Topics
  • Abnormalities, Multiple (genetics)
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Exons
  • Gene Expression
  • Heart Defects, Congenital (genetics)
  • Heart Septal Defects, Atrial (genetics)
  • Humans
  • Lower Extremity Deformities, Congenital (genetics)
  • Mice
  • Molecular Sequence Data
  • Muscle Cells (cytology, metabolism)
  • Muscle, Skeletal (growth & development, metabolism)
  • Mutation
  • Myocardium (metabolism, ultrastructure)
  • Protein Isoforms (analysis, genetics, metabolism)
  • Sequence Alignment
  • T-Box Domain Proteins (analysis, genetics, metabolism)
  • Upper Extremity Deformities, Congenital (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: