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(MRC DTP) The impact of centronuclear myopathy mutations in BIN1 on muscle function and structural organisation


Project Description

Transverse tubules are surface membrane invaginations in skeletal and cardiac muscle. They are the site where the major proteins involved in linking excitation (L-type calcium channels; DHPRs) to contraction (ryanodine receptors; RyRs) are located and are key to the efficient coupling of the action potential to force generation. Disruption of the transverse tubule network is known to contribute to the pathophysiology of both cardiac and skeletal muscle diseases.Understanding the mechanisms by which the formation of transverse tubules is controlled could provide novel therapeutic insight.
BIN1 (a.k.a AmphII) is regarded as one of the key proteins responsible not only for controlling transverse tubule formation but also for determining nuclear positioning in muscle cells. More specifically, we have previously shown in the heart that BIN1 drives transverse tubule formation and is required for transverse tubule maintenance[1,2]. Previous work by others has demonstrated similar importance of BIN1 in skeletal muscle transverse tubule biology [3], and mutations in BIN1 lead to skeletal muscle and cardiac pathology[4].
In addition to the role of BIN1 in skeletal muscle transverse tubule biology, mutations in BIN1 are also responsible for central nuclear myopathies (CNM) [4], a group of inherited conditions that lead to progressive skeletal muscle weakness and premature death. In CNM BIN1 missense mutations, deletions and exon skipping have been reported and exon 11 of BIN1, encoding a 15 amino acid phosphoinositide 3 kinase peptide sequence, has classically been considered as the exon that determines transverse tubule formation and nuclear positioning in skeletal muscle.
In addition to generating a number of heterologous expression vectors reflecting CNM point mutations and exon 11 skipping, we have generated two mouse models where exon 11 of BIN1 is either constitutively deleted or flanked by loxP sites allowing for inducible and tissue-specific exon deletion.
This project aims to use these mouse models and exogenous expression systems to understand how mutations in BIN1 lead to the skeletal and cardiac muscle phenotypes of CNM. The objectives are; i) to determine the role of BIN1 in driving nuclear positioning, transverse tubule architecture and the distribution of key calcium regulatory proteins (RyR and DHPR) in skeletal and cardiac muscle and, ii) to determine how these mutations affect in vivo muscle function. We will use a range of complementary in vivo and in vitro methods to assess the pathophysiological mechanisms of BIN1 mutations including muscle performance assays and advanced correlative super resolution (STORM) and electron microscopy techniques.

Professor Trafford: https://www.research.manchester.ac.uk/portal/andrew.w.trafford.html

Dr Dibb: https://www.research.manchester.ac.uk/portal/katharine.dibb.html

Dr Pinali: https://www.research.manchester.ac.uk/portal/christian.pinali.html

Professor Degens: https://www2.mmu.ac.uk/life-sciences/staff/profile/index.php?id=2013

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Caldwell, J.L., et al., Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ Res, 2014. 115(12): p. 986-996.
2. Lawless, M., et al., Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure. Sci Rep, 2019. 9(1): p. 6801.
3. Razzaq, A., et al., Amphiphysin is necessary for organization of the excitation-contraction coupling machinery of muscles, but not for synaptic vesicle endocytosis in Drosophila. Genes Dev, 2001. 15(22): p. 2967-79.
4. Böhm, J., et al., Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy. PLoS Genet, 2013. 9(6): p. e1003430.

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