Reading Frame Repair of TTN Truncation Variants Restores Titin Quantity and Functions.

ABSTRACT:

Background

Titin truncation variants (TTNtvs) are the most common inheritable risk factor for dilated cardiomyopathy (DCM), a disease with high morbidity and mortality. The pathogenicity of TTNtvs has been associated with structural localization as A-band variants overlapping myosin heavy chain-binding domains are more pathogenic than I-band variants by incompletely understood mechanisms. Demonstrating why A-band variants are highly pathogenic for DCM could reveal new insights into DCM pathogenesis, titin (TTN) functions, and therapeutic targets.

Methods

We constructed human cardiomyocyte models harboring DCM-associated TTNtvs within A-band and I-band structural domains using induced pluripotent stem cell and CRISPR technologies. We characterized normal TTN isoforms and vari

SUBMITTER: Romano R 

PROVIDER: S-EPMC8766920 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature