A novel mutant, apoA-I Nichinan (Glu235 -> 0), is associated with low HDL cholesterol levels and decreased cholesterol efflux from cells

A novel Variant of apolipoprotein (apo) A-I associated with low high densit y lipoprotein (HDL) cholesterolemia has been identified in a Japanese famil y during screening for apoA-I variants by isoelectric focusing (IEF) gel an alysis. ApoA-I (Glu235-->0) Nichinan was caused by a 3-bp deletion of nucle otides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma conce ntrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. Ther e were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, pla sma lecithin:cholesterol acyltransferase activity was normal. Functional co nsequences of the mutation were examined by expressing the mutated and wild -type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinan t proapoA-I Nichinan from mouse peritoneal macrophages loaded with [H-3]cho lesterol-labeled acetylated low density lipoprotein was decreased by 54% wh en compared that of normal recombinant proapoA-I, In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235-->0) Nichinan induced a critical structural c hange in the carboxyl-terminal domain of apoA-I for cellular cholesterol ef flux and increased the catabolism of apoA-I, resulting in low HDL cholester ol levels.