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A p.L13R mutation in nuclear envelope protein Lem2 results in cardiomyopathy and altered lipid handling in mice

James Black Centre, London

Title: A p.L13R mutation in nuclear envelope protein Lem2 results in cardiomyopathy and altered lipid handling in mice


The nuclear envelope (NE) is a double membrane barrier that segregates and protects the genome. Underlying the NE is a meshwork of structural proteins forming the nuclear lamina. Mutations in nuclear envelope/lamina proteins disproportionally result in striated muscle disorders, typically muscular dystrophies and dilated cardiomyopathies (DCM), highlighting the importance of these structures in mechanically active tissues. Such mutations are the second biggest cause of inherited DCM.

Recently, the inner nuclear membrane protein Lem2 was implicated in DCM with arrhythmia in a cohort of patients with a p.L13R mutation in this protein. Using a cardiomyocyte specific knockout of Lem2, our group demonstrated that Lem2 is essential for cardiac development in the mouse. We also generated a Lem2 p.L13R knock-in mouse which recapitulates many of the cardiac abnormalities found in patients, including thin ventricle walls, fibrosis and reduced cardiac function at baseline. Cellular studies of mutant cardiomyocytes reveal aberrant nuclei with a high propensity for envelope rupture. Unexpectedly, transcriptomics analysis and in vitro metabolic studies revealed defects in the metabolism of fatty acids, the major energy substrate of the heart. Further work will more precisely pinpoint the role of Lem2 in metabolic and genetic regulation, which might have therapeutic potential in patients with nuclear envelope defects.

Speaker: Dr Jacob Ross


Dr Jacob Ross is a postdoctoral researcher in Dr Matthew Stroud’s group at the James Black Centre. He carried out his PhD at University College London, focusing on the role of adhesion receptors in the development of skeletal muscle and the motor neuron synapse. Since then, he has been based at King’s College London, initially working on nuclear and contractile disorders of skeletal muscle, and currently on models of cardiomyopathy caused by mutations in nuclear envelope proteins.

Hosts: Anna Zoccarato, Joaquim Nunes Vieira, Giancarlo Forte

This is a hybrid event, taking place in the Large Seminar Room, Ground Floor, James Black Centre and via Microsoft Teams.

At this event

Jacob Ross

Research Associate

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