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

Jennifer England; Javier Granados-Riveron; Luis Polo-Parada; Diji Kuriakose; Christopher Moore; J. David Brook; Catrin S. Rutland; Kerry Setchfield; Christopher Gell; Tushar K. Ghosh; Frances Bu'Lock; Christopher Thornborough; Elisabeth Ehler; Siobhan Loughna

doi:10.1016/j.yjmcc.2017.03.006

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

Jennifer England, Javier Granados-Riveron, Luis Polo-Parada, Diji Kuriakose, Christopher Moore, J. David Brook, Catrin S. Rutland, Kerry Setchfield, Christopher Gell, Tushar K. Ghosh, Frances Bu'Lock, Christopher Thornborough, Elisabeth Ehler, Siobhan Loughna

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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.

Original language	English
Journal	Journal of Molecular and Cellular Cardiology
Early online date	27 Mar 2017
DOIs	https://doi.org/10.1016/j.yjmcc.2017.03.006
Publication status	E-pub ahead of print - 27 Mar 2017

Keywords

Cardiac development
Congenital heart defects
Structural protein
Tropomyosin 1

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10.1016/j.yjmcc.2017.03.006

Tropomysin 1 Multiple roles_ENGLAND_Accepted24March2017_GREEN AAMAccepted author manuscript, 1.34 MBLicence: CC BY-NC-ND

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England, J., Granados-Riveron, J., Polo-Parada, L., Kuriakose, D., Moore, C., Brook, J. D., Rutland, C. S., Setchfield, K., Gell, C., Ghosh, T. K., Bu'Lock, F., Thornborough, C., Ehler, E., & Loughna, S. (2017). Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects. Journal of Molecular and Cellular Cardiology. Advance online publication. https://doi.org/10.1016/j.yjmcc.2017.03.006

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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.",

keywords = "Cardiac development, Congenital heart defects, Structural protein, Tropomyosin 1",

author = "Jennifer England and Javier Granados-Riveron and Luis Polo-Parada and Diji Kuriakose and Christopher Moore and Brook, {J. David} and Rutland, {Catrin S.} and Kerry Setchfield and Christopher Gell and Ghosh, {Tushar K.} and Frances Bu'Lock and Christopher Thornborough and Elisabeth Ehler and Siobhan Loughna",

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doi = "10.1016/j.yjmcc.2017.03.006",

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England, J, Granados-Riveron, J, Polo-Parada, L, Kuriakose, D, Moore, C, Brook, JD, Rutland, CS, Setchfield, K, Gell, C, Ghosh, TK, Bu'Lock, F, Thornborough, C, Ehler, E & Loughna, S 2017, 'Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects', Journal of Molecular and Cellular Cardiology. https://doi.org/10.1016/j.yjmcc.2017.03.006

TY - JOUR

T1 - Tropomyosin 1: 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

PY - 2017/3/27

Y1 - 2017/3/27

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

U2 - 10.1016/j.yjmcc.2017.03.006

DO - 10.1016/j.yjmcc.2017.03.006

M3 - Article

SN - 0022-2828

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -

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

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Keywords

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