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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:460-467.)
© 1995 American Heart Association, Inc.

Articles

Two Different Allelic Mutations in a Finnish Family With Lecithin:Cholesterol Acyltransferase Deficiency

H. Miettinen; H. Gylling; I. Ulmanen; T. A. Miettinen; K. Kontula

From the Institute of Biotechnology (H.M.) and Department of Medicine (H.M., H.G., T.A.M., K.K.), University of Helsinki, Helsinki, Finland, and the Orion Corp (I.U.), Orion-Farmos, Orion Research, Helsinki, Finland.

Correspondence to Helena Miettinen, MD, Institute of Biotechnology, PO Box 45, Valimotie 7, SF-00014, University of Helsinki, Helsinki, Finland.

Abstract Lecithin:cholesterol acyltransferase (LCAT) deficiency is a genetic disorder associated with low levels of serum HDL cholesterol. The proband of the Finnish LCAT-deficient family had corneal opacities, proteinuria, anemia with stomatocytosis, low serum HDL cholesterol (0.27 mmol/L), and low LCAT activity. Sequence analysis of his LCAT gene revealed compound heterozygosity for two different mutations: a C insertion in exon 1 between nucleotides 932 and 937 and a C-to-T point mutation in exon 6 at position 4976. The C insertion in exon 1 is predicted to result in premature termination and a truncated polypeptide containing only 16 amino acids. The C-to-T point mutation in exon 6 substitutes cysteine for arginine at residue 399. The functional significance of the Arg³⁹⁹Cys mutation was examined by expressing the mutated and wild-type LCAT cDNAs in COS cells. COS cells transfected with mutated and wild-type cDNAs showed comparable levels of mature LCAT mRNA. However, LCAT activity in the cell media of COS cells transfected with the mutant LCAT cDNA was significantly lower than that of COS cells transfected with the wild-type cDNA (1.4% versus 12.0% cholesterol esterified, respectively). A polymerase chain reaction–based duplex assay, in which both mutations can be detected simultaneously, was used for preliminary screening of Finnish subjects with serum HDL levels below 0.9 mmol/L; two additional individuals heterozygous for the Arg³⁹⁹Cys mutation were identified. In conclusion, two different allelic mutations in the LCAT gene have been identified in a Finnish family, a C insertion between nucleotides 932 and 937 and a C-to-T transversion at position 4976, and a convenient polymerase chain reaction–based assay suitable for regional population screening and differential diagnosis of low serum HDL was developed.

Key Words: cholesterol esterification • fish-eye disease • lecithin:cholesterol acyltransferase • HDL • stomatocytosis

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