A HAND to TBX5 Explains the Link Between Thalidomide and Cardiac Diseases
| Autor: | Rachel Tanos, Georges Nemer, Patrice Bouvagnet, Nehme El-Hachem, Fadi Bitar, Mazen Kurban, Athar Khalil |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Heart Defects Congenital Male animal structures Heart disease Genotype Science Plasma protein binding Consanguinity Pharmacology Biology Article 03 medical and health sciences chemistry.chemical_compound medicine Basic Helix-Loop-Helix Transcription Factors Humans Gene Multidisciplinary HEK 293 cells Promoter DNA medicine.disease Pedigree Protein Structure Tertiary Thalidomide Molecular Docking Simulation 030104 developmental biology HEK293 Cells Phenotype chemistry embryonic structures Medicine Female T-Box Domain Proteins medicine.drug HeLa Cells Protein Binding |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
| ISSN: | 2045-2322 |
| Popis: | Congenital heart disease is the leading cause of death in the first year of life. Mutations only in few genes have been linked to some cases of CHD. Thalidomide was used by pregnant women for morning sickness but was removed from the market because it caused severe malformations including CHDs. We used both in silico docking software, and in vitro molecular and biochemical methods to document a novel interaction involving Thalidomide, TBX5, and HAND2. Thalidomide binds readily to TBX5 through amino acids R81, R82, and K226 all implicated in DNA binding. It reduces TBX5 binding to DNA by 40%, and suppresses TBX5 mediated activation of the NPPA and VEGF promoters by 70%. We documented a novel interaction between TBX5 and HAND2, and showed that a p.G202V HAND2 variant associated with CHD and coronary artery diseases found in a large Lebanese family with high consanguinity, drastically inhibited this interaction by 90%. Similarly, thalidomide inhibited the TBX5/HAND2 physical interaction, and the in silico docking revealed that the same amino acids involved in the interaction of TBX5 with DNA are also involved in its binding to HAND2. Our results establish a HAND2/TBX5 pathway implicated in heart development and diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|