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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:83-90.)
© 1997 American Heart Association, Inc.

Articles

Apolipoprotein A-I_Fin

Dominantly Inherited Hypoalphalipoproteinemia Due to a Single Base Substitution in the Apolipoprotein A-I Gene

Helena E. Miettinen; Helena Gylling; Tatu A. Miettinen; Jorma Viikari; Lars Paulin; Kimmo Kontula

the Institute of Biotechnology (H.E.M., L.P., K.K.) and the Department of Medicine (H.E.M.H.G., T.A.M., K.K.), University of Helsinki, and the Department of Medicine, University of Turku (J.V.), Finland.

Correspondence to Helena E. Miettinen, MD, Department of Medicine, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland. E-mail helena.miettinen@hyks.mailnet.fi.

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 (apo) 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.

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

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