A CYSTEINE-CONTAINING TRUNCATED APO A-I VARIANT ASSOCIATED WITH HDL DEFICIENCY

We identified a 50-year-old Japanese woman with a novel mutation in th e apolipoprotein (apo) A-I gene causing high-density lipoprotein (HDL) deficiency. The patient had extremely low HDL cholesterol and apo A-I levels (0.14 mmol/L and 0.8 mg/dL, respectively) but no evidence of c oronary heart disease. However, she had bilateral xanthomas of the Ach illes tendon, elbow, and knee joint as well as corneal opacities. Sodi um dodecyl sulfate-polyacrylamide gel electrophoresis of serum followe d by immunoblotting revealed that the patient's apo A-I had a lower mo lecular weight (24000) than normal apo A-I. A partial gene duplication encompassing 23 nucleotides was found by DNA sequence analysis, resul ting in a tandem repeat of bases 333 to 355 from the 5' end of exon 4. This tandem repeat caused a frameshift mutation with premature termin ation after amino acid 207. The frameshift gives rise to a predicted p rotein sequence that contains two cysteines. We designated this mutant as apo A-I-Sasebo. Apo A-I-Sasebo formed heterodimers with apo A-II a nd apo E in the patient's plasma and was associated with both the low- density lipoprotein and HDL fractions. The patient's cholesterol ester ification rate and lecithin-cholesterol acyltransferase activity were reduced to about 30% of normal, although specific enzyme activity was unaffected, suggesting that it remained functionally normal. In additi on, cholesteryl ester transfer activity was reduced to about half of n ormal. Thus, apo A-I-Sasebo was associated with complex derangements o f lipoprotein metabolism.