Moreover, neither haploinsufficiency nor a dominant negative mutation has been proven to be the underlying mechanisms of SOD1 mutant associated ALS, because all of the originally identified and most recently found mutants are missense mutations without loss-of-function and knocking out of SOD1 is not able to recapitulate disease phenotype either (14, 15, 21, 25). Here, SOD1 is linked to amyotrophic lateral sclerosis.