peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in tissues affected by amyotrophic lateral sclerosis. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation. Mutations Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in the pathogenesis of amyotrophic lateral sclerosis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphic variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the neurofilament network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human cases of amyotrophic lateral sclerosis. The second variant consisted of an amino acid substitution from aspartate to tyrosine as a result of a single point mutation in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in amyotrophic lateral sclerosis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms. Other clinical significance Peripherin may be involved in the pathology of insulin-dependent diabetes mellitus (or diabetes mellitus type 1) in animals; however, no direct linkage has been found in human patients. In a nonobese diabetic mouse model, peripherin has been found as a known autoantigen (See antigen). B cell clones reactive to peripherin have also been found in early stages of the disease. Since peripherin is expressed in both the peripheral nervous system and, in young animals, by islet beta cells, it is possible that the destruction of both peripheral nervous system elements and islet β-cells in