APOPROTEIN A METABOLISM IN TANGIER DISEASE

The metabolic defect in Tangier disease has been investigated in two homozygous family members. One patient was pretreated with large amounts of homologous HDL prior to the injection of [125I]HDL and the metabolism of the substituted HDL was analyzed by two-dimensional immunoelectrophoresis employing monospecific antisera against apoproteins A-I and A-II. In addition, the specific activities of the A apoproteins have been determined throughout the course of HDL catabolism. Radioactivity confined to apoproteins A-I and A-II decayed from the plasma monoexponentially with a T 1 2 of 7 h and 17 h, respectively; the specific activity of apoprotein A-I remained unchanged in the course of HDL catabolism, while that of apoprotein A-II constantly decreased. The cellular concentration of the A apoproteins in the epithelial cells of the jejunal mucosa was determined in cryostat sections of intestinal biopsy specimens obtained from the second homozygous Tangier patient and several control patients. Employing the direct immunofluorescence technique and fluorescein isothiocyanate-labeled antibodies (γ-globulins) against apoprotein A-I and apoprotein A-II, intense specific apoprotein A immunofluorescence was detected within the epithelial cells and the collecting lymph vessels of the intestinal mucosa. The pattern of immunofluorescence in the Tangier and control intestinal mucosas was indistinguishable. Thus, the intravascular depletion of the A apoproteins contrasts with their regular cellular concentration. Our studies link the defect in Tangier disease to apoprotein A-I. The inability of this apoprotein to associate with protein and/or lipid and to become a regular constituent of HDL has been identified as the biochemical defect in this disease. This abnormality is currently best explained by a structural mutation or a specific catabolic defect of apoprotein A-I. © 1978.