Myh7-flox Mouse

Myh7, encoding the myosin heavy chain (myosin-7), is a sarcomeric gene with fundamental functions in cardiac and skeletal muscle contraction. It is closely related to cardiomyopathy and skeletal muscle myopathy, and its expression is regulated by enhancers [1,6].

Variants in Myh7 are responsible for 1%-5% of dilated cardiomyopathy (DCM) cases. MYH7-related DCM is characterized by early onset, high phenotypic expression, low left-ventricular reverse remodeling, and frequent progression to end-stage heart failure, with heart failure complications being more common than ventricular arrhythmias [2]. In hypertrophic cardiomyopathy, aggregating predicted deleterious missense (pDM) variants in Myh7, rather than predicted loss-of-function (pLOF) variants, shows strong association with the disease [3]. The incomplete-penetrant Myh7 G256E mutation disrupts the transducer region of the S1 head, increases available myosin heads for contraction, leading to hypercontractility and elevated mitochondrial respiration [4]. Transgenic Myh7 R453C piglets develop cardiac hypertrophy, fibrosis, and cardiomyocyte loss, with activation of TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways [5]. Recessive Myh7 mutations cause a myopathy with features like infancy/childhood onset, axial/proximal weakness, spinal rigidity, and severe scoliosis [7]. Myh7 variants are also associated with complex congenital heart disease, expanding its phenotypic spectrum [8].

In conclusion, Myh7 is crucial for muscle contraction in the heart and skeletal muscles. Studies, especially those using transgenic models like piglets, have revealed its role in various cardiac and skeletal muscle-related diseases. Understanding Myh7 and its associated variants can provide insights into the mechanisms of these diseases and potentially lead to new therapeutic strategies.