MOLECULAR-GENETIC STUDY OF FINNS WITH HYPOALPHALIPOPROTEINEMIA AND HYPERALPHALIPOPROTEINEMIA - A NOVEL GLY(230)ARG MUTATION (LCAT(FIN)) OF LECITHIN-CHOLESTEROL ACYLTRANSFERASE (LCAT) ACCOUNTS FOR 5-PERCENT OF CASES WITH VERY-LOW SERUM HDL CHOLESTEROL LEVELS

In an attempt to identify genetic factors underlying extreme alteratio ns of serum HDL cholesterol (HDL-C) concentrations, we examined two pr obands with HDL-C levels <0.2 mmol/L and subsequently screened two lar ge 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 prop osed 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 Gly(230)Arg (LCAT(Fin)) mutation, and the second was homozygous for an Arg(399)Cys mutation we described previously. Trans ient expression of the mutant LCAT(Fin) cDNA in COS cells disclosed ma rkedly 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 Arg(399)Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn(291)Ser mutation was significantly (P<.05) higher in the lo w-HDL-C group (4.8%) than in the high-HDL-C group (1.6%). In addition, we identified 1 carrier of the intron 14G-->A mutation of cholesterol ester transfer protein (CETP) in the high-HDL-C group and subsequentl y demonstrated cosegregation of the mutant allele with elevated HDL-C levels in the proband's family. In conclusion, we have identified a no vel LCAT gene Gly(230)Arg mutation (LCAT(Fin)), which, together with t he LPL Asn(291)Ser mutation, represents a relatively common genetic ca use of diminishing HDL-C levels, at least among Finns. This article al so reports occurrence of a CETP mutation in subjects having non-Japane se roots.