Miettinen H E, Gylling H, Tenhunen J, Virtamo J, Jauhiainen M, Huttunen J K, Kantola I, Miettinen T A, Kontula K
Department of Medicine, University of Helsinki, Finland.
Arterioscler Thromb Vasc Biol. 1998 Apr;18(4):591-8. doi: 10.1161/01.atv.18.4.591.
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 14G-->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 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.
为了确定血清高密度脂蛋白胆固醇（HDL-C）浓度极端变化背后的遗传因素，我们研究了两名HDL-C水平<0.2 mmol/L的先证者，随后在两组大量吸烟男性队列中进行筛查，一组HDL-C水平极低（0.2至0.7 mmol/L，n = 156），另一组HDL-C水平升高（1.9至3.6 mmol/L，n = 160），以检测新发现的突变以及其他一些被认为会影响HDL-C水平的突变。其中一名先证者有角膜混浊、微量白蛋白尿、高甘油三酯血症和低密度脂蛋白载脂蛋白B浓度降低；另一名有贫血，外周血出现口形红细胞增多症。发现第一名先证者为一种新的卵磷脂胆固醇酰基转移酶（LCAT）Gly230Arg（LCAT[Fin]）突变的纯合子，第二名是我们先前描述的Arg399Cys突变的纯合子。突变型LCAT(Fin) cDNA在COS细胞中的瞬时表达显示LCAT酶活性明显降低。在HDL-C水平低的男性组（n = 156）中，鉴定出8名LCAT(Fin)携带者和1名LCAT Arg399Cys携带者。此外，脂蛋白脂肪酶（LPL）Asn291Ser突变的频率在HDL-C水平低的组（4.8%）中显著（P<0.05）高于HDL-C水平高的组（1.6%）。此外，我们在HDL-C水平高的组中鉴定出1名胆固醇酯转运蛋白（CETP）内含子14G→A突变的携带者，随后在该先证者家族中证明突变等位基因与升高的HDL-C水平共分离。总之，我们鉴定出一种新的LCAT基因Gly230Arg突变（LCAT[Fin]），它与LPL Asn291Ser突变一起，至少在芬兰人中代表了HDL-C水平降低的一个相对常见的遗传原因。本文还报道了非日本裔个体中发生的CETP突变。
