Apolipoprotein A-I-Fin - Dominantly inherited hypoalphalipoproteinemia due to a single base substitution in the apolipoprotein A-I gene

作者：Miettinen HE^*; Gylling H; Miettinen TA; Viikari J; Paulin L; Kontula K

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 1997, 17(1): 83-90.

• high-density lipoprotein
• catabolism
• mutation
• reverse cholesterol transport
• gene expression

We have identified a large kindred with severe serum HDL cholesterol deficiency. The proband, a 65-year-old woman, had greatly diminished concentrations 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 similarly reduced in all affected family members, while apo A-II levels were about half of those in the nonaffected family members. Pedigree analysis suggested a dominant inheritance pattern of the phenotype. Sequence analysis of the exons and exon-intron boundaries of the apo A-I gene revealed heterozygosity for a single T-to-G point mutation substituting 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 analysis of the mutation. All the affected family members were shown to be heterozygous for the apo A-I-Fin mutation. Isoelectric focusing revealed the presence of the mutant apo A-I-Fin protein in both serum and HDL of the affected subjects. Functional consequences of the mutation were examined by expressing the mutated and wild-type apo A-I cDNAs in COS-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 secreted into the cell media. In vivo kinetic studies of apo A-I revealed increased catabolism in affected subjects. In conclusion, we describe a novel point mutation of the apo A-I gene, apo A-I-Fin, causing a dominantly negative phenotype as regards serum HDL levels, possibly due to increased catabolism of apo A-I.

• 出版日期1997-1