Analysis of myopathy-linked titin genetic variants
Mutations in the gene encoding titin, TTN, have been linked to various muscle diseases including early onset myopathy and dilated cardiomyopathy. Due to it being so large, however, even healthy individuals will be likely to harbour mutations in their TTN gene. We have been investigating methods to distinguish these benign from disease-causing mutations, in particular by measuring the solubility and thermal stability of individual titin domains harbouring a missense variant. We typically find that, in contrast to benign variants, disease linked variants render their domain insoluble and/or reduce its thermal stability, and aggregate in cellular models.