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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 |
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Carl Peter
J. Maury, Knut Sletten, Nick Totty, Hannele Kangas, and Mikko Liljestrom
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Department
of Medicine (CPJM, HK, ML), University of Helsinki, Helsinki, Finland; Department
of Biochemistry (KS), Biotechnology Centre of Oslo, University of Oslo,
Oslo, Norway; and Structural Biology Laboratory (NT), Ludwig Institute of
Cancer Research, London, United Kingdom |
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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 (Asn-187).
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