More generically, domain swapping has been identified as a general possible initial mechanism for protein misfolding (41, 46), often being the conformational seed for the aggregation of a variety of proteins, including the human prion protein (52), β2-microglobulin (53, 54), cystatin C (55), amyotrophic lateral sclerosis (1), and antitrypsin deficiency (2). This evidence concerns the gene CST3 and amyotrophic lateral sclerosis.