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 the 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 coronary heart disease. However, she had bilateral xanthomas of the Achilles tendon, elbow, and knee joint as well as corneal opacities. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of serum followed by immunoblotting revealed that the patient's apo A-I had a lower molecular weight (24,000) than normal apo A-I. A partial gene duplication encompassing 23 nucleotides was found by DNA sequence analysis, resulting 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 termination after amino acid 207. The frameshift gives rise to a predicted protein sequence that contains two cysteines. We designated this mutant as apo A-ISasebo. Apo A-ISasebo formed heterodimers with apo A-II and apo E in the patient's plasma and was associated with both the low-density lipoprotein and HDL fractions. The patient's cholesterol esterification 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 addition, cholesteryl ester transfer activity was reduced to about half of normal. Thus, apo A-ISasebo was associated with complex derangements of lipoprotein metabolism.
Moriyama
K
K
Department of Internal Medicine, Fukuoka University, School of Medicine, Japan.
Sasaki
J
J
Takada
Y
Y
Matsunaga
A
A
Fukui
J
J
Albers
J J
JJ
Arakawa
K
K
D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D003545:Cysteine / Q000235:genetics; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000172:deficiency* / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D003545:Cysteine