APOLIPOPROTEIN A-I-FIN - DOMINANTLY INHERITED HYPOALPHALIPOPROTEINEMIA DUE TO A SINGLE-BASE SUBSTITUTION IN THE APOLIPOPROTEIN-A-I GENE

We have identified a large kindred with severe serum HDL cholesterol d eficiency. The proband, a 65-year-old woman, had greatly diminished co ncentrations of serum HDL cholesterol (0.19 mmol/L) and apolipoprotein (ape) A-I (21.9 mg/dL). HDL cholesterol and apo A-I levels were simil arly reduced in all affected family members, while apo A-II levels wer e about half of those in the nonaffected family members. Pedigree anal ysis suggested a dominant inheritance pattern of the phenotype. Sequen ce analysis of the exons and exon-intron boundaries of the apo A-I gen e revealed heterozygosity for a single T-to-G point mutation substitut ing arginine for leucine at residue 159 of the mature apo A-I protein (apo A-I-Fin). The T-to-G substitution destroys an Fsp I cleavage site , permitting direct polymerase chain reaction/restriction enzyme analy sis of the mutation. All the affected family members were shown to be heterozygous for the apo A-I-Fin mutation. Isoelectric focusing reveal ed the presence of the mutant apo A-I-Fin protein in both serum and HD L of the affected subjects. Functional consequences of the mutation we re examined by expressing the mutated and wild-type apo A-I cDNAs in C OS-7 cells. The mutant apo A-I mRNA had a size similar to that of the normal mRNA, and both mutant and wild-type apo A-I proteins were secre ted into the cell media. In vivo kinetic studies of apo A-I revealed i ncreased catabolism in affected subjects. In conclusion, we describe a novel point mutation of the apo A-I gene, apo A-I-Fin, causing a domi nantly negative phenotype as regards serum HDL levels, possibly due to increased catabolism of apo A-I.