Key result
Biallelic titin truncation variants promote cardiomyopathy by impairing sarcomere assembly and force in iPSC cardiomyocytes.
Why the study?
Biallelic titin truncation variants are linked to severe cardiac and skeletal muscle diseases, but the underlying mechanisms remain unclear.
iPSC-CM data from one biallelic TTNtv case warrant cautious interpretation; leaves open sarcomere mechanisms in dilated cardiomyopathy.
Biallelic titin truncation variants (TTNtvs) are linked to severe cardiac and skeletal muscle diseases, due to unclear mechanisms. Using induced pluripotent stem cell-derived cardiomyocytes from a biallelic TTNtv patient with dilated cardiomyopathy, we investigated sarcomere structure/function. Only the longest of the TTNtvs was detected as protein, and this nearly full-length titin was incorporated into the sarcomere. Subtle structural alterations occurred, with shortened A-bands observed in a subset of sarcomeres. Resulting reduction and imbalance of force development was linked to lowered contractility, and many sarcomeres being stretched by their neighbors. Thus, inefficient sarcomere assembly and interaction promotes cardiomyopathy in biallelic TTNtv.
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Erdal et al. (2026) studied Dilated cardiomyopathy with biallelic titin truncation variants (n=1). Biallelic titin truncation variants (TTNtvs) was evaluated on Sarcomere structure and function. Biallelic titin truncation variants in patient-derived iPSC cardiomyocytes led to inefficient sarcomere assembly, shortened A-bands, and reduced force development promoting cardiomyopathy.
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