Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion

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Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion. / Ehsan, Mehroz; Kelly, Matthew; Hooper, Charlotte; Yavari, Arash; Beglov, Julia; Bellahcene, Mohamed; Ghataorhe, Kirandeep; Poloni, Giulia; Goel, Anuj; Kyriakou, Theodosios; Fleischanderl, Karin; Ehler, Elisabeth; Makeyev, Eugene; Lange, Stephan; Ashrafian, Houman; Redwood, Charles; Davies, Benjamin; Watkins, Hugh; Gehmlich, Katja.

In: Journal of Molecular and Cellular Cardiology, Vol. 121, 08.2018, p. 287-296.

Research output: Contribution to journalArticle

Harvard

Ehsan, M, Kelly, M, Hooper, C, Yavari, A, Beglov, J, Bellahcene, M, Ghataorhe, K, Poloni, G, Goel, A, Kyriakou, T, Fleischanderl, K, Ehler, E, Makeyev, E, Lange, S, Ashrafian, H, Redwood, C, Davies, B, Watkins, H & Gehmlich, K 2018, 'Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion', Journal of Molecular and Cellular Cardiology, vol. 121, pp. 287-296. https://doi.org/10.1016/j.yjmcc.2018.07.248

APA

Ehsan, M., Kelly, M., Hooper, C., Yavari, A., Beglov, J., Bellahcene, M., Ghataorhe, K., Poloni, G., Goel, A., Kyriakou, T., Fleischanderl, K., Ehler, E., Makeyev, E., Lange, S., Ashrafian, H., Redwood, C., Davies, B., Watkins, H., & Gehmlich, K. (2018). Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion. Journal of Molecular and Cellular Cardiology, 121, 287-296. https://doi.org/10.1016/j.yjmcc.2018.07.248

Vancouver

Author

Ehsan, Mehroz ; Kelly, Matthew ; Hooper, Charlotte ; Yavari, Arash ; Beglov, Julia ; Bellahcene, Mohamed ; Ghataorhe, Kirandeep ; Poloni, Giulia ; Goel, Anuj ; Kyriakou, Theodosios ; Fleischanderl, Karin ; Ehler, Elisabeth ; Makeyev, Eugene ; Lange, Stephan ; Ashrafian, Houman ; Redwood, Charles ; Davies, Benjamin ; Watkins, Hugh ; Gehmlich, Katja. / Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion. In: Journal of Molecular and Cellular Cardiology. 2018 ; Vol. 121. pp. 287-296.

Bibtex

@article{9a6a3c1fe9c84395a494c3ed42fdd8ac,
title = "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion",
abstract = "Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations.",
keywords = "hypertrophic cardiomyopathy, Sarcomere, Proteasome, Protein depletion, RNAseq transcriptome analysis, MLP C58G mutation, Mouse knock-in model, In vivo phenotyping",
author = "Mehroz Ehsan and Matthew Kelly and Charlotte Hooper and Arash Yavari and Julia Beglov and Mohamed Bellahcene and Kirandeep Ghataorhe and Giulia Poloni and Anuj Goel and Theodosios Kyriakou and Karin Fleischanderl and Elisabeth Ehler and Eugene Makeyev and Stephan Lange and Houman Ashrafian and Charles Redwood and Benjamin Davies and Hugh Watkins and Katja Gehmlich",
note = "Copyright {\textcopyright} 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.",
year = "2018",
month = aug
doi = "10.1016/j.yjmcc.2018.07.248",
language = "English",
volume = "121",
pages = "287--296",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion

AU - Ehsan, Mehroz

AU - Kelly, Matthew

AU - Hooper, Charlotte

AU - Yavari, Arash

AU - Beglov, Julia

AU - Bellahcene, Mohamed

AU - Ghataorhe, Kirandeep

AU - Poloni, Giulia

AU - Goel, Anuj

AU - Kyriakou, Theodosios

AU - Fleischanderl, Karin

AU - Ehler, Elisabeth

AU - Makeyev, Eugene

AU - Lange, Stephan

AU - Ashrafian, Houman

AU - Redwood, Charles

AU - Davies, Benjamin

AU - Watkins, Hugh

AU - Gehmlich, Katja

N1 - Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2018/8

Y1 - 2018/8

N2 - Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations.

AB - Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations.

KW - hypertrophic cardiomyopathy

KW - Sarcomere

KW - Proteasome

KW - Protein depletion

KW - RNAseq transcriptome analysis

KW - MLP C58G mutation

KW - Mouse knock-in model

KW - In vivo phenotyping

U2 - 10.1016/j.yjmcc.2018.07.248

DO - 10.1016/j.yjmcc.2018.07.248

M3 - Article

C2 - 30048712

VL - 121

SP - 287

EP - 296

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -