High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in the Netherlands: Identification and characterization of eight novel mutations
High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in the Netherlands: Identification and characterization of eight novel mutations
复制标题
荷兰低 HDL 胆固醇水平患者中 LCAT 突变发生率较高：八种新突变的鉴定和表征
作者：
A. Holleboom;J. Kuivenhoven;F. Peelman;A. Schimmel;J. Peter;J. Defesche;J. Kastelein;G. Hovingh;E. Stroes;M. Motazacker
胆固醇酰基转移酶（LCAT）对高密度脂蛋白（HDL）的成熟至关重要。LCAT突变的纯合性是以HDL-胆固醇（HDL-c）缺乏为特征的罕见疾病的基础，而杂合子具有正常HDL-c水平的一半。我们研究了低HDL-c转诊患者中LCAT突变的患病率，以更好地了解我们患者中低HDL-c的分子基础。对98名HDL-c <第5百分位数的患者和4名低HDL-c和角膜混浊的患者进行了LCAT测序。LCAT突变非常普遍：在98名参与者中的28名（29%）中，确定了非同义突变的杂合性，而18名患者携带相同的突变（p.T147I）。4例角膜混浊患者为复合杂合子。所有先前鉴定的突变都记录为导致催化活性丧失。9个新突变-c.402G> T（p.E134D），c.403T> A（p.Y135N），c.964C> T（p.R322C），c.296G> C通过体外表征显示c.736G> T（p.V246F）、c.802C> T（p.R268C）、c.945G> A（p.W315X）、c.1012C> T（p.L338F）和c.1039C> T（p.R347C）--具有功能。通过三维（3D）模型研究了几种突变对核心蛋白结构的影响。与之前的报告不同，在29%的低HDL ‐ c患者中发现了LCAT的功能突变，因此构成了荷兰转诊患者中低HDL ‐ c的常见原因。Mutat 32：1290 - 1298，2011.© 2011 Wiley Periodicals，Inc.
Lecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high‐density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL‐cholesterol (HDL‐c) deficiency while heterozygotes have half normal HDL‐c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL‐c to better understand the molecular basis of low HDL‐c in our patients. LCAT was sequenced in 98 patients referred for HDL‐c <5th percentile and in four patients referred for low HDL‐c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal opacity were compound heterozygotes. All previously identified mutations are documented to cause loss of catalytic activity. Nine novel mutations—c.402G>T (p.E134D), c.403T>A (p.Y135N), c.964C>T (p.R322C), c.296G>C (p.W99S), c.736G>T (p.V246F), c.802C>T (p.R268C), c.945G>A (p.W315X), c.1012C>T (p.L338F), and c.1039C>T (p.R347C)–‐were shown to be functional through in vitro characterization. The effect of several mutations on the core protein structure was studied by a three‐dimensional (3D) model. Unlike previous reports, functional mutations in LCAT were found in 29% of patients with low HDL‐c, thus constituting a common cause of low HDL‐c in referred patients in The Netherlands. Hum Mutat 32:1290–1298, 2011. ©2011 Wiley Periodicals, Inc.
载脂蛋白 A-I(Zavalla) (Leu159-->Pro)：HDL 胆固醇缺乏与早发冠状动脉疾病相关。
DOI：
10.1161/01.atv.18.8.1242
发表时间：
1998
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Miller,M;Aiello,D;Pritchard,H;Friel,G;Zeller,K
通讯作者：
Zeller,K
低α脂蛋白血症的遗传学研究。
影响因子：
2.1
作者：
Byard,PJ;Borecki,IB;Glueck,CJ;Laskarzewski,PM;Third,JL;Rao,DC
通讯作者：
Rao,DC