Truncated titin proteins in dilated cardiomyopathy

Abstract

Truncating mutations in TTN result in both truncated titin proteins and reduced full-length titin in patient hearts.

Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due toTTNmutations

“…Further research on human TTNtv heart tissue is essential and should involve earlier stages of the disease to affirm that increasing tr-protein content worsens the disease and that tr-titin–positive aggregates play a pathomechanistic role. In support of the key findings of our study, a companion paper ( 41 ) also reports the presence of tr-titin proteins in patients with TTNtv-DCM and titin haploinsufficiency as combined pathomechanisms.…”

Exploring the Potential of Symmetric Exon Deletion to Treat Non-Ischemic Dilated Cardiomyopathy by Removing Frameshift Mutations in TTN

“…In a recent study McAfee et al, showed the presence of TTNtv in DCM patients and how this comes together with a reduced amount of full TTN in DCM hearts. This study supported the view that both dominant-negative forms of TTNtv and the haploinsufficiency of TTN , together with additional risk factors, contribute to the development of DCM and eventually lead to DCM in patients bearing truncations [ 45 ]. These findings were supported by a parallel study by Fomin and colleagues [ 38 ].…”

“…Another application of this approach is in the investigation of the correlation between the position of a mutation and the severity of the DCM phenotype. A variety of studies have focused on finding the relationship between the severity of DCM and the position of the mutation, focusing on (1) alternative splicing, (2) the alternative Cronos promoter (3), or the proximity to the C-terminus [ 12 , 20 , 45 ]. In a recent study McAfee et al, showed the presence of TTNtv in DCM patients and how this comes together with a reduced amount of full TTN in DCM hearts.…”

“…A PSI value close to zero indicates that the respective exon is absent from most transcripts. Mutations located in TTN exons with a low PSI usually lead to mild phenotypes [ 9 , 11 , 44 , 45 ]. Finally, exon size also needs to be considered.…”

Genetic Insights into Primary Restrictive Cardiomyopathy

“…The major cardiac phenotype caused by TTN mutations is DCM, however so far almost exclusively truncation variants are proven to be causative accounting for 30% of affected individuals with DCM [97,98]. Recently, multiple pathogenic mechanisms have been suggested including haploinsufficiency, truncated titin polypeptides as well as post-translational modifications of titin [99,100]. The role of missense variants is poorly understood, but at least for DCM their relevance as causative remains questionable; they may have a modifying effect [101].…”