TY - JOUR
T1 - Tropomyosin 1
T2 - Multiple roles in the developing heart and in the formation of congenital heart defects
AU - England, Jennifer
AU - Granados-Riveron, Javier
AU - Polo-Parada, Luis
AU - Kuriakose, Diji
AU - Moore, Christopher
AU - Brook, J. David
AU - Rutland, Catrin S.
AU - Setchfield, Kerry
AU - Gell, Christopher
AU - Ghosh, Tushar K.
AU - Bu'Lock, Frances
AU - Thornborough, Christopher
AU - Ehler, Elisabeth
AU - Loughna, Siobhan
N1 - Funding Information:
The authors would like to thank Dr. Sophie Rochette, Sue Willington, Jamie Webster, Dr. Sally Wheatley, Dr. Paul Scotting, Denise McLean and Maria Haig, for technical assistance and helpful discussions. Imaging support was provided by the School of Life Sciences Imaging Unit, using a DeltaVision Elite System funded by a Welcome Trust Equipment Grant (094233/Z/10/Z). We thank Mr. Trevor Gray and Mr. Gusztav Istvan Velicsek for excellent assistance with electron microscopy and electronic artwork, respectively. The CT3 antibody developed by J.J. Lin was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242.
Publisher Copyright:
© 2017
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - Cardiac development
KW - Congenital heart defects
KW - Structural protein
KW - Tropomyosin 1
UR - http://www.scopus.com/inward/record.url?scp=85016433134&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2017.03.006
DO - 10.1016/j.yjmcc.2017.03.006
M3 - Article
C2 - 28359939
AN - SCOPUS:85016433134
SN - 0022-2828
VL - 106
SP - 1
EP - 13
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -