Titinis the largest protein in mammals, ranging from 2970 to ∼3700 kDa depending onisoformcomposition. It is encoded by a single gene located on the long arm ofchromosome 2, region 2q31 consisting of 363 exons[11,20–22]. As shown inFig. 1,titin'sN-terminus is anchored in the Z-...
Loss-of-function truncations in the titin gene are a common cause of DCM.6,14 Prompted by this evidence, we and others have speculated that a fraction of titin missense variants could also result in protein loss of function leading to DCM.12,13,14 However, to date, only three titin miss...
Based on the available genetic data, no evident copy number variants (CNVs) or variants in the triplicated region of theTTNgene were found intranswith the heterozygousTTNvariant. However, to further exclude compound heterozygosity for aTTNdefect abolishing the titin C-terminal, we used western blott...
Other cardiac structural genes have recently been associated with AF. Two different variants in the sarcomere protein gene myosin light chain 4 (MYL4) have in three independent studies been associated with familial early-onset AF9,10,27. Gudbjartsson et al.10performed whole-genome sequencing of ...
The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human...
The first antenatal-onset titinopathy presented with multi-minicore disease (MmD), arthrogryposis, left ventricular non-compaction and ventricular septal defect, and was associated with the first-reported absence of a functional titin kinase domain in humans. Other novel phenotypes associate MmD with ...
(Gautel et al., 1996; Guo et al., 2010; Lange et al., 2006). As humans have only one titin gene, thisisoformregulation occurs by alternative splicing (Bang et al., 2001). Misregulation of titin splicing, for example by a mutation in the RNA-binding protein RBM20, results in severe...