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Understanding the link between the shape of nuclei and DNA organisation in muscle cells from people living with laminopathy  

Professor Francesco Saverio Tedesco and his PhD student at University College London aim to understand if changes in the shape of nuclei in muscle cells of people with laminopathies cause the loss of organisation of DNA.
Details
Principal Investigator
Professor Francesco Saverio Tedesco
Institute
University College London (UCL)
Official title
Linking Form to Function: Modelling and Investigating Downstream Effects of Nuclear Shape Abnormalities in Laminopathies
Duration
Four years
Total cost
£148,889
Conditions
Charcot-Marie-Tooth disease (CMT) Emery-Dreifuss muscular dystrophy (EDMD) Limb girdle muscular dystrophy (LGMD) Limb girdle muscular dystrophy R1 (LGMDR1) Previous name: LGMD2A Limb girdle muscular dystrophy R2 (LGMDR2) Previous name: LGMD2B Limb girdle muscular dystrophy R9 (LGMDR9) Previous name: LGMD2I Limb girdle muscular dystrophy sarcoglycanopathies (LGMDR3, LGMDR4, LGMDR5, LGMDR6) Previous names: LGMD2D, LGMD2E, LGMD2C, LGMD2F LMNA-related congenital muscular dystrophy (LMNA-CMD)
Year
2024

Background

The LMNA gene makes proteins called lamin A/C. Genetic changes to LMNA cause conditions called laminopathies, which affect a variety of organs, particularly the heart and the muscles. Each cell has a nucleus, a round-shaped structure in which DNA is stored. Lamin A/C proteins form a structure called the nuclear lamina, which is critical to maintaining the structure of the cell nucleus.  

DNA inside the nucleus is not randomly distributed but is organised in a careful manner, with help of the nuclear lamina. One of the cellular features most associated with laminopathies is changed nuclear shape. This occurs in muscle cells when there is a problem with lamin proteins, because muscles are a part of the body that moves frequently, meaning a lot of force and physical stress is placed on the muscle cells.  

Professor Tedesco and his team have developed a model of muscles under laboratory conditions. These are called mini-muscles – read more here. In this new study, the team will isolate nuclei of particular shapes from mini-muscles made from cells taken from people who live with laminopathies. They will use methods for ‘reading’ the genes, broadly called sequencing, to see if changes in nuclear shape have any effect on the organisation of DNA.  

What are the aims of the project?

As well as isolating nuclei of different shapes from laminopathy cells and checking if changes in shape correlate with changes in DNA organisation, the team will also test if muscle contractions have an impact on DNA organisation. Further on, the aim will be to find any potential treatments that can increase muscle function through improving DNA organisation.

The importance of this study

This research will increase our understanding of the causes of laminopathies. These findings might help Professor Tedesco and his team design and develop new treatments to manage the condition.