The TTN gene codes for the largest known protein in the human body, titin. This protein, which is also known as connectin, is found in sarcomeres, the basic units of striated muscle tissue. The protein is made up of the elastic I-band at the N-terminal and the kinase A-band at the C-terminal. It connects the Z-line to the M-line in the sarcomere, by binding its N-terminal Z-disc region and its C-terminal M-line region to the Z-line and M-line respectively. The titin protein thus spans half the length of the sarcomere and acts as a molecular spring responsible for the elasticity of muscles. It acts along with myosin and actin to keep the components of the sarcomere in place and is necessary for the stability and flexibility of the unit. The protein also contains sites for binding with other proteins, is involved in chemical signaling, and is speculated to function in chromosome condensation during mitosis.
The gene is implicated in several disorders of myopathy and muscular dystrophy. It has been associated with Cardiomyopathy, Dilated, 1G (CMD1G), Cardiomyopathy, Familial Hypertrophic, 9 (CMH9), Muscular Dystrophy, Limb-Girdle, Type 2J (LGMD2J), Myopathy, Early-Onset, with Fatal Cardiomyopathy (EOMFC), Hereditary Myopathy with Early Respiratory Failure (HMERF) and Tibial Muscular Dystrophy, Tardive (TMD).
The TTN gene, located on the long arm of chromosome 2, spans a length of 304.8 kb of DNA. Its coding sequence is contained in 364 exons, which is the largest number of exons discovered in a single gene. The protein product encoded by TTN has a molecular mass of 3816 kDa and contains 34350 amino acids. Several different muscle-specific isoforms of the TTN protein exist due to alternative splicing. While these isoforms differ in their I-band, M-line and the Z-disc regions, it is the variability in the I-band that accounts for the difference in elasticity of different muscle types. The gene is found to be overexpressed in the adult and fetal heart as well as the skeletal muscles.
Homozygous mutations in the TTN gene are associated with limb-girdle muscular dystrophy type 2J and early-onset myopathy with fatal cardiomyopathy while heterozygous mutations are linked to dilated cardiomyopathy 1G, familial hypertrophic cardiomyopathy 9, hereditary myopathy with early respiratory failure and tardive tibial muscular dystrophy.
Al-Shamsi et al. (2016) evaluated 85 patients at a metabolic center in Abu Dhabi that had failed to be diagnosed using conventional methods. Whole Exome Sequencing (WES) helped diagnose 50% of these cases. In one patient from a consanguineous family, WES uncovered variants of unknown significance in the TTN gene. The compound heterozygous mutations c.9160G>C (p.A24878V), c.68120A>G (p.E3054), and c.74633C>T (p.Y22707C) were confirmed to be pathogenic due to a consistent phenotype, biochemical findings and reported pathogenicity. While the parents were asymptomatic, it was found that the mother was heterozygous for c.9160G>C and c.68120A>G and the father was heterozygous for c.74633C>T.