Molecular Genetic Study of Finns With Hypoalphalipoproteinemia and Hyperalphalipoproteinemia: Cholesterol Acyltransferase (LCAT) Accounts for 5% of Cases With Very Low Serum HDL Cholesterol Levels

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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 Gly230 Arg (LCATFin) mutation, and the second was homozygous for an Arg399 Cys mutation we described previously. Transient expression of the mutant LCATFin cDNA in COS cells disclosed markedly diminished LCAT enzyme activity. In the low-HDL-C group of men (n=156), 8 carriers of LCATFin and 1 carrier of the LCAT Arg399 Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn291 Ser 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 14G[right arrow]A 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 Gly230 Arg mutation (LCATFin), which, together with the LPL Asn291 Ser 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. (Arterioscler Thromb Vasc Biol. 1998;18:591-598.)

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