Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a disease pathogenetically and clinically similar to that caused by the 654G-A mutation (familial amyloidosis of the Finnish type)

Background-Familial amyloidosis of the Finnish type (FAF, Finnish hereditar y amyloidosis) is caused by a 654G-A mutation in the gelsolin gene on chrom osome 9 resulting in the expression of mutant Asn-187 gelsolin which is abn ormally proteolytically processed generating amyloidogenic fragments that p olymerise into amyloid fibrils. We have: recently shown that in a Danish an d a Czech family with a clinical syndrome similar to FAF, including corneal lattice dystrophy, cranial neuropathy and skin changes, the disease is cau sed by another mutation at the same position, namely 654G-T predicting a Ty r-for-Asp substitution at 187 in secreted gelsolin. Aim-To undertake a closer examination of the Danish subtype of FAF and repo rt immunohistochemical and biochemical findings. Results-Immunostaining of plasma gelsolin isolated from heterozygous FAF of the Danish subtype revealed a pattern similar to that found in FAF-Asn 187 . The > 60 kDa gelsolin species contain an epitope characteristic of the am yloid forming region as revealed by an amyloid specific antibody, whereas t he similar to 50 kDa fragments are devoid of it. Compared with the wild-typ e gelsolin peptide (Asp-187), the corresponding mutant peptide (Tyr-187) sh owed dramatically increased fibrillogenicity as revealed by quantitative th ioflavine-T based fluorimetry; ultrastructurally, amyloid-like fibrils were formed by the mutant peptide. Immuno-histochemistry showed that antibodies directed against residues 231-242 of secreted gelsolin, representing the c arboxy terminus of the sequence forming the amyloid protein (residues 173-2 43) laid down in the tissues in a fibrillar form in FAF, specifically label led the amyloid deposited in rectum and skin in the Danish (654G-T) subtype . Conclusions-The 654G-T mutation in the gelsolin gene gives rise to an amylo id disease clinically and pathogenetically similar to that caused by the 65 4G-A mutation.