Tangier disease: defective recombination of a specific Tangier apolipoprotein A-I isoform (pro-apo A-i) with high density lipoproteins.
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.
D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D001053:Apolipoproteins / Q000097:blood* / Q000302:isolation & purification; D001054:Apolipoproteins A; D005260:Female; D006801:Humans; D007009:Hypolipoproteinemias / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood*; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis; D011498:Protein Precursors; D013631:Tangier Disease / Q000097:blood*
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D001053:Apolipoproteins; D001054:Apolipoproteins A; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D011498:Protein Precursors