Apo A-IMiu,. is a mutant form of apo A-I in which cysteine is substituted for arginine at amino acid 173. Subjects with apo A-IMih... are characterized by having low levels of plasma HDL cholesterol and apo A-I. To determine the kinetic etiology of the decreased plasma levels of the apo A-I in these individuals, normal and mutant apo A-I were isolated, radiolabeled with either 1251 or 131I, and both types of apo A-I were simultaneously injected into two normal control subjects and two subjects heterozygous for apo A-Im,.... In the normal subjects, apo A-IMil.. was catabolized more rapidly than the normal apo A-I (mean residence times of 5.11 d for normal apo A-I vs. 3.91 d for apo A-Imj.,,), clearly establishing that apo A-IMj,,.O is kinetically abnormal and that it has a shortened residence time in plasma. In the two apo A-Imi,. subjects, both types of apo A-I were catabolized more rapidly than normal (residence times ranging from 2.63 to 3.70 d) with normal total apo A-I production rates (mean of 10.3 vs. 10.4 mg/kg per d in the normal subjects). Therefore, in the subjects with apo A-Imo, the decreased apo A-I levels are caused by rapid catabolism of apo A-I and not to a decreased production rate, and the abnormal apo A-IMi,. leads to the rapid catabolism of both the normal and mutant forms of apo A-I in the affected subjects. (J. Clin.

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Tangier disease is a rare familial disorder characterized by extremely low levels of apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). In normal subjects, proapoA-I is secreted into plasma and converted to mature apoA-I by the cleavage of the amino-terminal six amino acids with the major isoprotein in plasma being mature apoA-I. In contrast, in Tangier disease there is a marked relative increase of proapoA-I as compared with mature apoA-I. ProapoA-I and mature apoA-I were isolated from normal and Tangier disease subjects, radiolabeled, and autologous apoA-I isoproteins injected into normal and Tangier subjects. The in vivo catabolism and conversion of proapoA-I and mature apoA-I in normal and Tangier disease subjects were quantitated. A comparison of the rate of catabolism of apoA-I isoproteins from plasma revealed a significantly faster rate of catabolism of both isoproteins of apoA-I in Tangier subjects when compared with normal subjects. The fractional conversion rate of proapoAI to mature apoA-I was 3.9 d' in normal subjects and 3.6 d ' in Tangier subjects. The results indicate that (a) apoA-I enters plasma as the pro isoprotein in both normal and Tangier subjects, (b) Tangier disease subjects have a normal fractional rate of conversion of proapoA-I to mature apoA-I, (c) proapoA-I is catabolized at the same rate as mature apoA-I in Tangier subjects, and (d) Tangier subjects catabolize both pro and mature apoA-I at a much greater rate than do normal subjects. Therefore, the relative increase in proapoA-I in Tangier disease is due to a marked decrease in mature apoA-I resulting from rapid catabolism of both pro-and mature apoA-I and not to defective conversion of proapoA-I to mature apoA-I.

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