Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects

Abstract

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1 + 2T > C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1 + 2T > C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs.

Tropomyosin-1 promotes cancer cell apoptosis via the p53-mediated mitochondrial pathway in renal cell carcinoma

“…In the present study, TPM1 overexpression in RCC inhibited tumor cell proliferation and promoted tumor cell apoptosis. The present results are consistent with several previous investigations which have reported an association between TPM1 overexpression and increased apoptosis rate in oral squamous cell carcinoma, cholangiocarcinoma and in some benign diseases, such as congenital heart defects ( 11 – 13 ). In the present study, multiple standard methods were used to detect cell apoptosis, including morphological changes by DAPI staining and fluorescence microscopy, DNA fragments detected by comet assay, cytomembrane instability by flow cytometry, and caspase-3 protein expression by western blotting.…”

Combining Nanomaterials and Developmental Pathways to Design New Treatments for Cardiac Regeneration: The Pulsing Heart of Advanced Therapies

“…Mutations in the titin gene (TTN) are the most common causes of pathogenicity (∼25-27.6% of familial and 11.6-18% of sporadic cases) (Schafer et al, 2016). Other frequent mutations affect MYH7 (Colegrave and Peckham, 2014), tropomyosin a1 chain (TPM1) (England et al, 2017), and the genes of cardiac troponins (TNNT2) (Hershberger et al, 2009).…”

Avian Cardiovascular Disease Characteristics, Causes and Genomics

“…In total the myosins, cardiac myosin binding protein C and troponin gene account for over 90% of the known causative mutations in human hypertrophic cardiomyopathy [94], for example. Tropomyosin I, which is associated with both actin and troponin T has also been shown to present with cardiomyopathy associated mutations in humans and more recently abnormal atrial septation, ventricular trabeculae and looping in genetic knockdown developing chickens [95]. Given the research already present in some of these genes in avian species, and their high sequence homology and expression patterns in avian cardiac tissue they present excellent candidate genes for further investigation.…”