Molecular Genetic Study of Finns With Hypoalphalipoproteinemia and Hyperalphalipoproteinemia

A Novel Gly²³⁰Arg Mutation (LCAT_Fin) of Lecithin:Cholesterol Acyltransferase (LCAT) Accounts for 5% of Cases With Very Low Serum HDL Cholesterol Levels

From the Department of Medicine, University of Helsinki (H.E.M., H.G., T.A.M., K.K.); Orion Research, Orion Corp Biocenter, Helsinki (J.T.); National Public Health Institute, Helsinki (J.V., M.J., J.K.H.); and Department of Medicine, University of Turku (I.K.), Finland.

Correspondence to Kimmo Kontula, MD, Professor of Molecular Medicine, Department of Medicine, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland.

Abstract—In an attempt to identify genetic factors underlying extreme alterations of serum HDL cholesterol (HDL-C) concentrations, we examined two probands with HDL-C levels <0.2 mmol/L and subsequently screened two large cohorts of smoking men, one with very low (0.2 to 0.7 mmol/L, n=156) and the other with elevated (1.9 to 3.6 mmol/L, n=160) HDL-C levels, for the newly detected mutations as well as some other mutations proposed to affect HDL-C levels. One of the probands had corneal opacities, microalbuminuria, hypertriglyceridemia, and reduced LDL apoprotein B concentration; the other had anemia and presented with stomatocytosis in his peripheral blood. The first proband was found to be homozygous for a novel LCAT Gly²³⁰Arg (LCAT_Fin ) mutation, and the second was homozygous for an Arg³⁹⁹Cys mutation we described previously. Transient expression of the mutant LCAT_Fin cDNA in COS cells disclosed markedly diminished LCAT enzyme activity. In the low–HDL-C group of men (n=156), 8 carriers of LCAT_Fin and 1 carrier of the LCAT Arg³⁹⁹Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn²⁹¹Ser mutation was significantly (P<.05) higher in the low–HDL-C group (4.8%) than in the high–HDL-C group (1.6%). In addition, we identified 1 carrier of the intron 14GA mutation of cholesterol ester transfer protein (CETP) in the high–HDL-C group and subsequently demonstrated cosegregation of the mutant allele with elevated HDL-C levels in the proband's family. In conclusion, we have identified a novel LCAT gene Gly²³⁰Arg mutation (LCAT_Fin), which, together with the LPL Asn²⁹¹Ser mutation, represents a relatively common genetic cause of diminishing HDL-C levels, at least among Finns. This article also reports occurrence of a CETP mutation in subjects having non-Japanese roots.

Key Words: HDL cholesterol • LCAT deficiency • lipoprotein lipase • cholesterol ester transfer protein • mutation

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