Identification of the circulating amyloid precursor and other gelsolin metabolites in patients with G654A mutation in the gelsolin gene (Finnish familial amyloidosis): pathogenetic and diagnostic implications.
Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant type of systemic amyloidosis caused by a G654A (Asn-187) or G654T (Tyr-187) mutation in the gelsolin gene. Herein we show that patients with the Asn-187 gelsolin mutation have, in addition to full-sized gelsolin, a series of lower-Mr C-terminal fragments of gelsolin (Mr of 70,000-45,000) in the circulation, and that a 50 to 55-kd fragment of gelsolin is excreted in the urine. In homozygous FAF (Asn-187), the 65-kd fragment, which contains the amyloid-forming region (Ala173-Met243), and the 55-kd fragment, which is devoid of that region, are the major gelsolin species in plasma; whereas normal gelsolin, as well as a 70-kd fragment identified as the C-terminal portion of gelsolin starting at Glu122, and a 45-kd fragment starting at Ser384, are minor components. In patients heterozygous for the Asn-187 mutation--the usual form of the expression of the dominant disease--normal-sized gelsolin is the major circulating form; the 65- and 55-kd fragments represent minor components. Immunodetection of the plasma 65-kd gelsolin fragment, which is disease-specific, and measurement of the urinary gelsolin fragment provide useful means for diagnosing FAF.
Maury
C P
CP
Department of Medicine, University of Helsinki, Finland.
Sletten
K
K
Totty
N
N
Kangas
H
H
Liljeström
M
M
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000097:blood*; D000686:Amyloidosis / Q000235:genetics*; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D002846:Chromatography, Affinity; D018260:Gelsolin / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D018260:Gelsolin