Mutations (D187N/Y) in the second domain of gelsolin trigger the proteolytic pathway producing amyloidogenic fragments that form the pathological hallmark of gelsolin amyloidosis and lattice corneal dystrophy type 2 (LCD2).
Our study included 8 cases of acquired monoclonal immunoglobulin light chain amyloidosis, 11 cases of transthyretin amyloidosis (3 with the Val30Met mutation, 2 with the Val32Ala mutation, 2 with the Thr60Ala mutation, 1 with the Ala109Ser mutation, 1 with the Phe64Leu mutation, 1 with the Ala97Ser mutation, and 1 not sequenced), and 2 cases of gelsolin amyloidosis (1 with the Asp187Asn mutation and 1 not sequenced).
The present study demonstrates the first successful in vitro creation of amyloid-like fibrils from Asn187 gelsolin peptides and provides evidence that amyloid formation in Finnish amyloidosis is a direct consequence of the Asp187----Asn substitution in gelsolin.
The gelsolin fragments isolated from at least one patient with amyloidosis have been reported to have an amino acid substitution, with asparagine replacing aspartic acid at position 187 of the plasma gelsolin.