Mutations in the Sensitive Giant Titin Result in a Broken Heart

Truncations of Titin Causing Dilated Cardiomyopathy Herman et al N Engl J Med. 2012;366:619–628.The specialized cytoskeleton of striated muscle cells consists of highly ordered structures, the single contractile units termed sarcomeres. Although once believed to be simply a scaffold for the assembly of structural proteins to generate force and motion, it is now widely recognized that the sarcomeric cytoskeleton is dynamic and is intimately involved in numerous cellular signaling processes that respond to a wide range of extracellular cues. Sarcomeres in vertebrates are built of an intricate array of myosin-containing thick filaments, actin-containing thin filaments, and titin filaments (Figure, A), along with a plethora of other structural and regulatory proteins. Titin (also known as connectin) is the largest protein discovered in humans to date.1,2 The human titin gene is enormous; at 363 exons, it encompasses the largest number of exons in any single gene and is predicted to encode up to 38 138 residues, or a 4.2-MDa protein.3 Remarkably, a single molecule of titin spans half the length of a sarcomere with its NH2 terminus embedded in the Z-disc and its COOH terminus anchored at the center of the sarcomere, the M-line (Figure, A). This corresponds to a molecular length of approximately 0.9 to >1.5 μm, depending on sarcomere stretch! Because titin filaments from opposite half-sarcomeres fully overlap in the Z-discs and at the M-line, titin filaments form a continuous system within myofibrils.Figure. Striated muscle sarcomere (Panel A) with locations of titin mutations linked to human dilated cardiomyopathy (Panel B). Mutations are markedly missing from the Z disc and M line; they are highly enriched in the thick filament associated A band region. While some patients presented with identical mutations, numbers reflect unique mutations.Although many unique functions for titin have been described, it is most known for its function as a molecular spring; it limits …