Tangier disease is a rare familial disorder characterized by enlarged orange tonsils, transient
peripheral neuropathy, hepatosplenomegaly, and
lymphadenopathy, as well as striking reductions in plasma
high density lipoproteins (HDL) and their major
protein constituents,
apolipoproteins (
apo)A-I and A-II. In order to test the hypothesis that Tangier patients have abnormal
apoA-I or
apoA-II, the in vitro
lipoprotein binding and in vivo metabolic characteristics of these
proteins isolated from normal and Tangier plasma, were studied in normal subjects and patients with
Tangier disease. After incubation with normal plasma, significantly greater percentages of radiolabeled Tangier
apoA-I were associated with the 1.063-g/ml supernate (6%) and the 1.21 g/ml infranate (19%), and a lower percentage with HDL (75%), than those observed for normal
apoA-I (2, 8, and 90%, respectively). In contrast, the
lipoprotein binding properties of normal and Tangier
apoA-II were very similar. Following the injection of radiolabeled normal and Tangier
apoA-I into normal subjects (n = 4), the mean residence times of the specific activity for
apoA-I(Tangier) were significantly lower, both in plasma (1.29 d) and in HDL (1.34 d), than those observed for normal
apoA-I (3.80 and 4.06 d). In Tangier homozygotes the decay rates of these tracers were very rapid and were similar. No significant differences between the kinetics of normal and Tangier
apoA-II were observed in normal subjects (n = 2). Tangier homozygotes (n = 3) had mean plasma
HDL cholesterol,
apoA-I, and
apoA-II concentrations that were 4, 2, and 11% of normal (n = 24), respectively, whereas for heterozygotes (n = 3) these values were 46, 62, and 68% of normal. In homozygotes, in contrast to normals or heterozygotes, a significant fraction of both
apoA-I and
apoA-II were found in the 1.063-g/ml supernate instead of in HDL. Homozygotes had
apoA-I(Tangier) synthesis rates and residence times that were 41 and 5% of values observed for normal
apoA-I in normal subjects, and for
apoA-II in homozygotes, these parameters were 63 and 18% of normal. Heterozygotes had
apoA-I synthesis rates and residence times that were 92 and 66% of normal, and for
apoA-II these values were 101 and 64% of normal. These data are consistent with the concept that
apoA-I(Tangier) is functionally and metabolically distinct from normal
apoA-I, and is the cause of the striking hypercatabolism of
apoA-I and
apoA-II, and the
lipoprotein abnormalities observed in
Tangier disease.