TTN

Gene Summary

This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

Clinical Phenotype

Titinopathies: include LGMD2J/R10 (tibial muscular dystrophy — Finnish distal myopathy), hereditary myopathy with early respiratory failure (HMERF), Udd myopathy, and dilated cardiomyopathy. Some variants contribute to idiopathic DCM.

Molecular Mechanism

Titin is the largest human protein, spanning the entire sarcomere from Z-disc to M-line. It functions as a molecular spring, contributing to passive elasticity. Truncating variants are common in dilated cardiomyopathy (~25% of familial DCM). Recessive compound heterozygotes develop severe LGMD.

Clinical Hallmarks & Key Evidence

External Resources