Speaker Dr Martin Rees, Research Associate, Gautel Lab, The Randall Centre, KCL

Title The identification and molecular characterisation of pathogenic missense variants in the massive muscle protein titin

Host Elisabetta Brunello

 

Abstract Titin is a massive, multidomain protein expressed in skeletal and cardiac muscle that spans half a sarcomere, the basic contractile unit of muscle. Variants in the gene encoding titin, TTN, are increasingly linked with a range of myopathies, but ascertaining the pathogenicity of these can be difficult due to the prevalence of TTN variants in the general population and their sometimes-complex inheritance patterns. I will present work from the group of Mathias Gautel that has helped distinguish benign from disease-causing titin missense variants using biophysical assays that show pathogenic missense variants frequently destabilise their domain. Analysis of in vivo models and cells expressing fragments of titin has begun to shed light on how these variants convey their pathogenic effects. Finally, I will present preliminary data detailing attempts to prevent destabilisation of missense variant-carrying domains by the in silico design of proteins that bind to these regions of titin.