title: 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.
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: England
authors.affiliation: Laboratory of Genomics, Genetics and Bioinformatics, Hospital Infantil de México Federico Gómez, Mexico.
authors.forename: Javier
authors.initials: J
authors.lastname: Granados-Riveron
authors.affiliation: Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Polo-Parada
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: Diji
authors.initials: D
authors.lastname: Kuriakose
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Moore
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, UK.
authors.forename: Catrin S
authors.initials: CS
authors.lastname: Rutland
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Setchfield
authors.affiliation: School of Life Sciences Imaging, University of Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gell
authors.affiliation: School of Life Sciences, University of Nottingham, UK.
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Ghosh
authors.affiliation: East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Bu'Lock
authors.affiliation: East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Thornborough
authors.affiliation: Randall Division of Cell and Molecular Biophysics, The Cardiovascular Division, King's College London, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehler
authors.affiliation: School of Life Sciences, University of Nottingham, UK. Electronic address: Siobhan.Loughna@nottingham.ac.uk.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Loughna
mesh_terms: D000199:Actins / Q000235:genetics; D005260:Female; D006321:Heart / Q000254:growth & development* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006352:Heart Ventricles / Q000254:growth & development / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D000199:Actins; D012322:RNA Precursors; C490775:TPM1 protein, human; D014335:Tropomyosin; D018995:Myosin Heavy Chains
keywords: Cardiac development; Congenital heart defects; Structural protein; Tropomyosin 1