In vivo metabolism of a mutant apolipoprotein, apoA-IIowa, associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis.
Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). A kindred has been identified in which a glycine to arginine mutation at residue 26 in apoA-I is associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. We isolated the mutant protein, termed apoA-IIowa, from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-IIowa subjects and two normal controls. Normal and mutant apoA-I were radioiodinated with 131I and 125I, respectively, reassociated with autologous plasma lipoproteins, and simultaneously injected into all subjects. Kinetic analysis of the plasma radioactivity curves demonstrated that the mutant apoA-IIowa was rapidly cleared from plasma (mean fractional catabolic rate [FCR] 0.559 day-1) compared with normal apoA-I (mean FCR 0.244 day-1) in all four subjects. The FCR of normal apoA-I was also substantially faster in the heterozygous apoA-IIowa subjects (mean FCR 0.281 days-1) than in the normal controls (mean FCR 0.203 days-1). Despite the rapid removal from plasma of apoA-IIowa, the cumulative urinary excretion of its associated radioactivity after 2 weeks (44%) of the injected dose) was substantially less than that associated with normal apoA-I (78% of injected dose), indicating extravascular sequestration of radiolabeled apoA-IIowa.(ABSTRACT TRUNCATED AT 250 WORDS)
Rader
D J
DJ
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Gregg
R E
RE
Meng
M S
MS
Schaefer
J R
JR
Zech
L A
LA
Benson
M D
MD
Brewer
H B
HB
D000328:Adult; D000686:Amyloidosis / Q000097:blood / Q000235:genetics*; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D007009:Hypolipoproteinemias / Q000097:blood / Q000235:genetics*; D015151:Immunoblotting; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D009154:Mutation
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D001120:Arginine; D005998:Glycine