Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM.
In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM.
Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.
Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM.
Variants in the GATA4 gene have been implicated in several congenital heart diseases (CHD), such as the tetralogy of Fallot (ToF), atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and dilated cardiomyopathy (DCM).
Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.
Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM.
The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.
Myocardin (24.88 +/- 4.93 vs. 3.98 +/- 1.12, P = 0.0048) and GATA4 (17.85 +/- 4.85 vs. 0.45 +/- 0.15, P = 0.0069 x 10(-5)) were upregulated in IDCM patients compared with controls, whereas SERCA2 (5.11 +/- 0.42 vs. 8.93 +/- 1.07, P = 0.001) was downregulated.