Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene

Abstract

The amyloid protein in Finnish hereditary amyloidosis is a fragment of the actin-filament binding region of a variant gelsolin molecule. Here we demonstrate, using polymerase chain reaction and allele-specific oligonucleotide hybridization analyses of genomic DNA, a single base mutation @Y4+Ads4) in the gelsolin gene segment encoding the amyloid protein. The mutation is responsible for the expression of the variant (Asn1a7) gelsolin molecule in Finnish hereditary amyloidosis. The nucleotide substitution was found in all five unrelated patients with Finnish amyloidosis studied, but not in 45 unrelated control subjects. The mutation co-segregated with the disease phenotype in a family with Finnish amyloidosis. The results show that a single substitution in the gelsolin gene causes Finnish hereditary amyloidosis. The allele-specific oligonucleotide hybridization method provides a simple and accurate means of detecting this mutation.

Gelsolin-related amyloidosis. Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin.

“…At position 15 of the amyloid proteins an asparagine was found instead of the predicted aspartic acid residue in gelsolin (position 187; reference 12). A point mutation in the gelsolin gene causing the expression of the mutant asparagine-187 gelsolin molecule in Finnish FAP was recently reported from this laboratory (13).…”

“…However, this possibility seems likely, because previous studies have shown that single amino acid substitutions in the amyloid precursor proteins, transthyretin in FAP type I and II and some related syndromes (21)(22)(23)(24)(25)(26)(27)(28)(29)(30), apolipoprotein A-I in FAP type III (31) and cystatin C in Icelandic hereditary amyloidosis (32), are all associated with the development of amyloid in these diseases. Moreover, we have recently demonstrated a point mutation in the gelsolin gene that is responsible for the expression of the mutant asparagine-187 gelsolin molecule in patients with Finnish FAP (13).…”

Gelsolin is a dorsalizing factor in zebrafish

“…Both forms of gelsolin are expressed in most adult tissues (14). Nucleotide substitution of G654 to A654 (15) gives rise to Finnish type familial amyloidosis (FAF), an autosomal-dominant disease characterized by corneal lattice dystrophy, skin changes, renal complications, and a cranial neuropathy that affects the cranial nerves in particular (16). In the developing rat brain, initial low levels of gelsolin precede increased expression around day 10 followed by a subsequent decrease near day 30, suggesting a functional role for gelsolin in early brain development (17).…”

Destabilization of Ca2+-free gelsolin may not be responsible for proteolysis in Familial Amyloidosis of Finnish Type

“…Both amyloid and intermediates of assembly have been implicated as causative agents in these diseases (12)(13)(14)(15). Deposition of a fragment of mutated human plasma gelsolin (173-243) putatively causes Familial Amyloidosis of Finnish Type (FAF), a disease characterized by lattice corneal dystrophy, progressive cranial neuropathy, and skin elasticity complications (16)(17)(18).Gelsolin is an actin-binding protein that nucleates, caps, and severs actin filaments. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and Ca 2ϩ ions regulate gelsolin's dissociation from and binding to actin, respectively (19)(20)(21)(22).…”

“…Both amyloid and intermediates of assembly have been implicated as causative agents in these diseases (12)(13)(14)(15). Deposition of a fragment of mutated human plasma gelsolin (173-243) putatively causes Familial Amyloidosis of Finnish Type (FAF), a disease characterized by lattice corneal dystrophy, progressive cranial neuropathy, and skin elasticity complications (16)(17)(18).…”