Resulting embryos show a direct relationship between a Noonan SHP-2 mutation and its ability to cause cardiac defects in Xenopus; embryos expressing Noonan SHP-2 mutations exhibit morphologically abnormal hearts, whereas those expressing an SHP-2 JMML-associated mutation do not.
To further define the role of a T-box transcription factor, Tbx5, in cardiac development, we have examined its expression in the developing mouse and chick heart and correlated this pattern with cardiac defects caused by human TBX5 mutations in Holt-Oram syndrome.
The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction.
In contrast, pharmacological activation of SIRT1 reduced the SERCA2a acetylation, which was accompanied by recovery of SERCA2a function and cardiac defects in failing hearts.
Interestingly, nrg1 mutant hearts were missing long axons on the ventricle surface by standard length (SL) 5 mm, which preceded juvenile and adult cardiac defects.
Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.
This raises concern that intolerance for further DMPK loss may limit ASO therapy, especially since mice with Dmpk gene deletion reportedly show cardiac defects and skeletal myopathy.
In our study, we evaluated the distribution of putative functional variants in a wider panel of 158 genes previously associated with arrhythmic and cardiac defects in a cohort of 91 SCN5A-negative BrS patients.
Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism.
These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.
Herein, we studied the molecular etiology of cardiac defects in Nos3(-/-) mice via transcriptional analysis of stage-matched embryonic tissues and iPSC-derived cells.
Depletion of both fibulin-7B and TMEM87B resulted in more severe defects of cardiac development, suggesting that their concurrent loss may enhance the risk of a severe cardiac defect.
In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency.