Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I.
Six unrelated families with genetically determined structural variants of apo A-I were found in the course of an electrophoretic screening program for apo A-I variants in dried blood samples of newborns. The following structural variations were identified by the combined use of HPLC, time-of-flight secondary ion mass spectrometry (TOF-SIMS), and automated gas phase sequencing: Pro3----Arg (1x), Pro4----Arg (1x), and Pro165----Arg (4x). All variant carriers were heterozygous for their mutant of apo A-I. Subjects heterozygous for apo A-I(Pro165----Arg) (n = 12) were found to exhibit lower mean values for apo A-I (109 +/- 16 mg/dl) and HDL cholesterol (37 +/- 9 mg/dl) than unaffected family members (n = 9): 176 +/- 41 and 64 +/- 18 mg/dl, respectively (P less than 0.001). In 9 of 12 apo A-I(Pro165----Arg) variant carriers the concentrations of apo A-I were below the fifth percentile of sex-matched controls. By two-dimensional immunoelectrophoresis as well as by densitometry the relative concentration of the variant apo A-I in heterozygous carriers of apo A-I(Pro165----Arg) was determined to account for only 30% of the total plasma apo A-I mass instead of the expected 50%. Thus, the observed apo A-I deficiency may be largely a consequence of the decreased concentration of the variant apo A-I. In the case of the apo A-I(Pro3----Arg) mutant, densitometry of HDL apolipoproteins demonstrated a distinctly increased concentration of the variant proapo A-I relative to normal proapo A-I. This phenomenon was not observed in the apo A-I(Pro4----Arg) mutant or in other mutants. This suggests that the interspecies conserved proline residue in position 3 of mature apo A-I is functionally important for the regular enzymatic conversion of proapo A-I to mature apo A-I.
von Eckardstein
A
A
Institut für Arterioskleroseforschung, Universität Münster, Federal Republic of Germany.
Funke
H
H
Henke
A
A
Altland
K
K
Benninghoven
A
A
Assmann
G
G
D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics*; D001120:Arginine; D008076:Cholesterol, HDL / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010375:Pedigree; D010446:Peptide Fragments; D011392:Proline / Q000235:genetics*
D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D010446:Peptide Fragments; D001120:Arginine; D011392:Proline