In vivo metabolism of a mutant form of apolipoprotein A-I, apo A-IMilano, associated with familial hypoalphalipoproteinemia.
Apo A-IMilano is a mutant form of apo A-I in which cysteine is substituted for arginine at amino acid 173. Subjects with apo A-IMilano are characterized by having low levels of plasma HDL cholesterol and apo A-I. To determine the kinetic etiology of the decreased plasma levels of the apo A-I in these individuals, normal and mutant apo A-I were isolated, radiolabeled with either 125I or 131I, and both types of apo A-I were simultaneously injected into two normal control subjects and two subjects heterozygous for apo A-IMilano. In the normal subjects, apo A-IMilano was catabolized more rapidly than the normal apo A-I (mean residence times of 5.11 d for normal apo A-I vs. 3.91 d for apo A-IMilano), clearly establishing that apo A-IMilano is kinetically abnormal and that it has a shortened residence time in plasma. In the two apo A-IMilano subjects, both types of apo A-I were catabolized more rapidly than normal (residence times ranging from 2.63 to 3.70 d) with normal total apo A-I production rates (mean of 10.3 vs. 10.4 mg/kg per d in the normal subjects). Therefore, in the subjects with apo A-IMilano, the decreased apo A-I levels are caused by rapid catabolism of apo A-I and not to a decreased production rate, and the abnormal apo A-IMilano leads to the rapid catabolism of both the normal and mutant forms of apo A-I in the affected subjects.
Roma
P
P
Molecular Disease Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Gregg
R E
RE
Meng
M S
MS
Ronan
R
R
Zech
L A
LA
Franceschini
G
G
Sirtori
C R
CR
Brewer
H B
HB
D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D005260:Female; D006579:Heterozygote; D006801:Humans; D007009:Hypolipoproteinemias / Q000378:metabolism*; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D009154:Mutation; D013631:Tangier Disease / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D014280:Triglycerides; C080631:apolipoprotein A-I Milano; D002784:Cholesterol