Disease severity in hereditary cardiac arrhythmias explained by non-coding variants?

Samenvatting

A mutation in one copy of the KCNQ1 gene causes cardiac arrhythmias that can suddenly kill the carrier. It is unclear why in family members carrying exactly the same mutation these cardiac arrhythmias vary greatly. We propose that this variation is caused by differences in the balance in expression between the healthy and mutated allele, which can be caused by variants in the 3? UTR.
Indeed, we found that 50% of the family members carried variants in the 3?UTR of KCNQ1 that suppress translation. When these variants reside on the mutated allele, this suppresses formation of the mutated protein and decreases cardiac arrhythmias. This novel mechanism largely explains the variation in disease severity.4 We further show that these variants create binding sites allowing microRNA-378 to suppress that specific allele. We aim to study how microRNA-378 alters allelic balance and electrophysiological properties in human iPS-cell derived cardiomyocytes obtained from mutation carriers who also carry the above 3?UTR variants. We anticipate to test whether inhibition of microRNA-378 can shift the allelic balance away from the mutated protein. If confirmed, this opens the exciting possibility to inhibit microRNA-378 as a novel therapy tailored at individual genomic variants to shift the allelic balance to the normal protein.
Keywords: long QT syndrome, microRNA-378, induced pluripotent stem cells, allele-specific effects, single nucleotide polymorphisms

Kenmerken

Projectnummer

825.13.007

Hoofdaanvrager

Dr. A.J.M. Tijsen

Verbonden aan

Technion - Israel Institute of Technology, The Schnis Research Laboratory for cardiac electrophysiology, The Bruce Rappaport Faculty of Medicine

Uitvoerders

Dr. A.J.M. Tijsen

Looptijd

01/10/2013 tot 21/03/2016