B6-hTTN Mouse

The TTN gene provides instructions for making titin, the largest known protein in the human body, essential for the structure, flexibility, and stability of sarcomeres, the fundamental contractile units of muscle ^[1]. Titin is primarily expressed in striated muscle, including skeletal muscle and cardiac muscle, where it acts as a molecular spring and scaffold, interacting with other muscle proteins like actin and myosin to maintain sarcomere integrity during muscle contraction and relaxation ^[2]. The TTN gene undergoes extensive alternative splicing, leading to the production of various titin isoforms with differing elastic properties, which contributes to the diverse mechanical characteristics of different muscle types. Mutations in TTN are a leading cause of various muscle and heart disorders, collectively known as titinopathies. These include familial dilated cardiomyopathy (DCM), a common cause of heart failure characterized by weakening and enlargement of the heart, often due to truncating variants in TTN. Other associated conditions include early-onset myopathy with fatal cardiomyopathy, centronuclear myopathy, limb-girdle muscular dystrophy, and tibial muscular dystrophy ^[3].

The B6-hTTN mouse is a humanized model constructed via gene-editing technology. The sequence from the ATG start codon to the TAA stop codon of mouse Ttn will be replaced with the sequence from the ATG start codon to the TAA stop codon of human TTN. B6-hTTN mice can be used to study the pathogenesis of hereditary muscle diseases such as familial dilated cardiomyopathy (DCM), early-onset myopathy, and muscular dystrophy, as well as for the screening, development, and safety evaluation of TTN-targeted drugs.