Isoforms of
apolipoprotein A-I (
apo A-I) from subjects with
Tangier disease were characterized, and their ability to recombine with normal
high density lipoproteins (HDL) was studied. In contrast to normal serum, in which isoprotein 4 is the dominant species [79 +/- 1.8% (mean +/- SD)], the Tangier serum contained much less total
apo A-I (approximately equal to 1% of that in normal serum), and isoproteins 2 and 4 were present in roughly equivalent amounts (35.3 +/- 2.5% and 42.7 +/- 3.6%, respectively). The Tangier isoprotein 2 was shown to correspond to
pro-apo A-I, having a six-
amino acid amino-terminal extension with the sequence: Arg-
His-Phe-Trp-Gln-Gln-. The Tangier isoprotein 4 had the same amino-terminal sequence as normal circulating plasma
apo A-I. Its association with normal HDL (70%) was similar to the association of normal
apo A-I with HDL (80-90%) in recombination experiments. In marked contrast to this behavior, very little (less than 10%) of Tangier isoprotein 2 (
pro-apo A-I) associated with HDL in recombination experiments. These results suggest that the underlying defect in
Tangier disease may be a faulty conversion of
pro-apo A-I to mature
apo A-I, either due to a defect in the converting
enzyme activity or to a further specific structural defect in
Tangier apo A-I. The failure of Tangier
pro-apo A-I to associate with HDL may be at least partially responsible for the HDL deficiency in Tangier subjects.