MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes. Issue 3 (16th March 2020)

• Record Type: Journal Article
• Authors: Lee, Yee-Ki; Sala, Luca; Mura, Manuela; Rocchetti, Marcella; Pedrazzini, Matteo; Ran, Xinru; Mak, Timothy S H; Crotti, Lia; Sham, Pak C; Torre, Eleonora; Zaza, Antonio; Schwartz, Peter J; Tse, Hung-Fat; Gnecchi, Massimiliano
• Is Part Of: Cardiovascular research. Volume 117:Issue 3(2021)
• Page Start: 767
• Page End: 779
• Publication Date: 2020-03-16
• Subjects: Long QT syndrome -- Induced pluripotent stem cells -- Arrhythmias -- Variants -- Nedd4L -- MTMR4; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvaa019
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action. Methods and results: We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1 -Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 ( MTMR4 ) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects. Conclusion: Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.