A B S T R A C T In this study we have determined by radioimmunoassay and double immunoelectrophoresis the total quantities and distributions of A apoproteins in three adtult patients affected with Tangier disease (hereditary a-lipoprotein deficiency). Compared with normal plasma, the total quantities of apoproteins A-I and A-II in Tangier plasma were determined to be <1% and 5-7%, respectively. In Tangier patients, approximately 90% of the apoprotein A-I sedimented when ultracentrifugations of plasma were carried out at density 1.21 g/ml KBr. By contrast, more than 95% of the apoprotein A-II floated under those conditions. In normal plasma, approximately 90% of both apoproteins A-I and A-II is found in the 1.063-1.21-g/ml KBr density fraction. These findings suggest that complete dissociation of A apoproteins occurs in Tangier plasma. This dissociation of apoproteins was confirmed by double immunoelectrophoresis with monospecific antisera. Immunochemical and electrophoretic experiments did not provide evidence for a structural abnormality of apoprotein A-I in these patients. The results taken together strongly suggest that normal high-density lipoproteins are absent from Tangier plasma.

A B S T RACT In this study a large family group affected with Tangier disease has been investigated. Besides two homozygous propositi, several heterozygous patients have been identified on the basis of quantitative measurements of high density lipoproteins and their constitutive polypeptides. By a variety of quantitative immunological methods, such as one-dimensional Laurell electrophoresis, two-dimensional immunoeletrophoresis, and double-antibody radioimmunoassay, the total amount of apoprotein A-I and apoprotein A-II contained in the serum of heterozygous patients and the distribution of these A apoproteins among serum lipoproteins have been determined. The molar ratio of apoprotein A-I and apoprotein A-II contained in high density lipoproteins ofheterozygous patients did not significantly differ from that of control preparations, although the total mass of high density lipoproteins was reduced by approximately 50%. The elution profile of high density lipoproteins from agarose columns and their morphological appearance, as ascertained by electron microscopy, were similar to control preparations. In addition to the quantitative alterations of serum lipoproteins, lipid storage in histiocytes of the rectal mucosa obtained from heterozygous patients has been documented. It is concluded that patients heterozygous for Tangier disease have normal high density lipoproteins in circulation, the total mass of which is reduced by approximately 50%.

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High density lipoprotein (HDL) infusion and partial plasma exchange were undertaken in two patients homozygous for Tangier disease. Serum samples and ultracentrifugally isolated serum fractions were analysed over a period of 7 days post infusion by agarose electrophoresis, two-dimensional immunoelectrophoresis (employing antibodies to HDL, HDL3, Apoprotein A-I, and Apoprotein A-II), Apoprotein A radioimmunoassay, and analytical polyacrylamide electrophoresis. The following observations were made: (a) immediately after HDL substitution the broad-beta band, normally visible upon agarose electrophoresis of Tangier plasma, resolved into a distinct beta and pre-beta band; (b)as HDL was catabolized, an abnormal alpha-migrating lipoprotein was generated which contained Apoprotein A-II as protein constituent; and (c) there was a proferential loss of Apoprotein A-I from HDL and the plasma compartment in the course of HDL catabolism. The results suggest that the defect in Tangier disease resides with enhanced catabolism or defective synthesis of Apoprotein A-I.