Molecular Analysis of Apolipoprotein A-I and E Mutants in Japan

Summary

We characterized four apoA-I deficiencies and eleven apoA-I structural mutations. Homozygous apoA-I (Vall56Glu) Oita was associated with apoA-I and HDL deficiencies, partial LCAT deficiency and corneal opacities. A compound heterozygous mutant of A to C substitution at position-27 in TATA box in addition to common G to A substitution at position-75 with nonsense mutation at residue 84 of apo A-I gene may contribute to apoA-I deficiency. ApoA-I(Glu235del)Nichinan induced a critical structural change of the C-terminal domain of apoA-I for cellular cholesterol efflux and increased catabolism of apoA-I, resulting in low HDL cholesterol level. We characterized three novel apoE mutations associated with lipoprotein glomerulopathy (LPG). LPG is a novel disease characterized by proteinuria, lipoprotein thrombi in glomeruli, and increased concentration of plasma apoE. We demonstrated that mutation of apoE gene is etiologically related to LPG. However, our cases indicate that other genetic or environmental factors seem to be necessary for the development of LPG. Identification of naturally occurring apolipoprotein variants allows understanding the role of apolipoproteins and the mechanism of dyslipoproteinemia.