Kuivenhoven J A, van Voorst tot Voorst E J, Wiebusch H, Marcovina S M, Funke H, Assmann G, Pritchard P H, Kastelein J J
Department of Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands.
J Clin Invest. 1995 Dec;96(6):2783-91. doi: 10.1172/JCI118348.
This paper describes a novel genetic defect which causes fish-eye disease in four homozygous probands and its biochemical presentation in 34 heterozygous siblings. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a near total loss of plasma lecithin:cholesterol acyltransferase (LCAT) activity. Sequencing of the LCAT gene revealed homozygosity for a novel missense mutation resulting in an Asp131 - Asn (N131D) substitution. Heterozygotes showed a highly significant reduction of HDL-cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant LCAT(N131D) against proteoliposomes. Unlike other mutations causing fish-eye disease, recombinant LCAT(N131D) also showed a 75% reduction in specific activity against LDL. These unique biochemical characteristics reveal the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and the specific loss of activity against HDL. The impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the male probands.
本文描述了一种导致4名纯合先证者患鱼眼病的新型基因缺陷及其在34名杂合子同胞中的生化表现。男性索引患者表现为早发性冠状动脉疾病、角膜混浊、高密度脂蛋白（HDL）缺乏以及血浆卵磷脂胆固醇酰基转移酶（LCAT）活性几乎完全丧失。对LCAT基因进行测序发现，存在一个导致Asp131 - Asn（N131D）替代的新型错义突变纯合子。与对照组相比，杂合子的HDL胆固醇和载脂蛋白A-I水平显著降低，这与LpA-I:A-II颗粒的特异性减少有关。对该突变的功能评估显示，重组LCAT（N131D）对蛋白脂质体的特异性活性丧失。与其他导致鱼眼病的突变不同，重组LCAT（N131D）对低密度脂蛋白（LDL）的特异性活性也降低了75%。这些独特的生化特征揭示了LCAT基因缺陷在LCAT活性完全丧失和对HDL活性特异性丧失所规定范围内的表型表达异质性。这种突变对HDL水平和HDL亚类分布的影响可能与男性先证者中观察到的早发性冠状动脉疾病有关。
