Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/9033
Modelling the heterogeneity and complex inheritance of Left Ventricular Non-Compaction
Date of defense
The compaction or formation of a thick and smooth cardiac ventricular wall is a fundamental process for cardiac function. This process takes place during late gestation and early postnatal period, and it is regulated by intercellular signalling from endocardium that controls myocardial proliferation and maturation. During compaction, the transient trabeculae that allowed cardiac growth in early development give rise to the cardiac conduction system, and are integrated in the thick compact wall. Defects in this process of compaction give rise to left ventricular non-compaction or LVNC. This cardiomyopathy can range from asymptomatic to causing arrhythmia or heart failure, even requiring heart transplantation. In addition, LVNC has been described isolated or combined with other congenital heart diseases (CHD), such as hypertrophic cardiomyopathy (HCM) or bicuspid aortic valve (BAV). The most common genetic causes underlying this disease are mutations in sarcomeric genes, but mutations affecting MIB1 (MIB1R530X and MIB1V943F), a member of the NOTCH signalling pathway, were recently identified by our lab as causative of LVNC in two different families. LVNC was observed in mice lacking Mib1 expression in the myocardium, confirming its importance in chamber development. As defects in NOTCH signalling pathway have also been described as causing BAV, we aimed at generating mouse models with the point mutations found in MIB1 by CRISPR-Cas9 to investigate the mechanisms underlying LVNC. These mouse lines allowed us to confirm that the inactivating mutation (Mib1R530X) showed LVNC when combined with the conditional heterozygous null allele in the myocardium, while the missense mutation (Mib1V943F) did not cause LVNC, but affected valve development when combined with heterozygous NOTCH inactivating mutations. These findings and the genetic and phenotypic heterogeneity of LVNC led us to hypothesise that there were other candidate mutations masked behind the autosomal dominant inheritance pattern. We performed exome sequencing in the families carrying the mentioned MIB1 variants, and could identify polymorphisms affecting novel candidates as APCDD1 and ASXL3 in one family, and CEP192, TMX3 and BCL7A in the other. The generation of mouse lines harbouring each set of mutations allowed us to identify new genes implicated in LVNC (Mib1R530X/+ Apcdd1V150I/+ Asxl3M1416V/+ mice) or in BAV (Mib1V943F/+ Cep192T1522M/+ Tmx3-204F191X/+ mice). Further analysis of these lines and the combination of the last one with the Bcl7a mutant, could help elucidating the distinct molecular mechanisms behind the variability of the severity or the ones that cause combined with CHD or isolated LVNC.
Files in this item
- Tesis Marcos Siguero.pdf