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Background. Light chain amyloidosis (AL) is caused by the overproduction, misfolding and aggregation of immunoglobulin light chains (LCs) that tend to deposit as amyloid fibrils in the cardiac tissue 1. Nowadays, the molecular details underling LCs soluble cardiotoxicity and fibril formation remain to be fully elucidated. It has been suggested a relationship between conformational flexibility and amyloidogenicity, indicating protein thermal stability and dynamics as factors able to influence the complex processes of misfolding and aggregation 2,3. To date, no compelling correlations have been identified between LCs cardiotoxicity and primary sequence. Here we present a pivotal mutagenesis study in which we produce and characterise a mutated variant of the toxic H6 LC (mH6). Our purpose is to abrogate the toxicity typical of H6 yielding to a non-cardiotoxic LC and to understand the biophysical and biochemical changes underlying such loss of toxicity.

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