Yang X P, Inazu A, Honjo A, Koizumi I, Kajinami K, Koizumi J, Marcovina S M, Albers J J, Mabuchi H
Second Department of Internal Medicine, School of Medicine, Kanazawa University, Ishikawa, Japan.
J Lipid Res. 1997 Mar;38(3):585-91.
Plasma lecithin:cholesterol acyltransferase (LCAT) plays an important role in early steps of reverse cholesterol transport, i.e., cholesterol efflux from peripheral tissues and cholesterol esterification in HDL. However, structural and functional relationships of LCAT have not been fully elucidated. We described a missense mutation of Gly 30-to-Ser in a patient with classical LCAT deficiency. The proband was homozygous for the mutation and had a very low level of HDL cholesterol (2 mg/dl), with a half of normal LCAT mass (2.75 micrograms/ml), but no detectable or very low LCAT activity in endogenous and exogenous substrate assays. Both his mother and sister were heterozygous for the mutation, and had slightly decreased levels of HDL cholesterol (34 and 36 mg/dl, respectively). Transient expression study using COS cells indicated that mutant cDNA produces similar amounts of media protein as compared to wild type, but no detectable LCAT activity. The missense mutation may result in a near-native conformation without large effects on cellular secretion but a catalytically defective protein. Thus, the N-terminal domain appears crucial for enzymatic activity, in addition to the catalytically active consensus sequence of Gly179 to Gly183 and a putative sterol binding domain of Glu154 to Lys173.
血浆卵磷脂胆固醇酰基转移酶（LCAT）在胆固醇逆向转运的早期步骤中起重要作用，即胆固醇从外周组织流出以及高密度脂蛋白（HDL）中的胆固醇酯化。然而，LCAT的结构与功能关系尚未完全阐明。我们描述了一名经典LCAT缺乏症患者中Gly 30突变为Ser的错义突变。先证者为该突变的纯合子，高密度脂蛋白胆固醇水平极低（2mg/dl），LCAT质量为正常水平的一半（2.75微克/毫升），但在内源性和外源性底物检测中未检测到或仅有极低的LCAT活性。他的母亲和姐姐均为该突变的杂合子，高密度脂蛋白胆固醇水平略有降低（分别为34和36mg/dl）。使用COS细胞进行的瞬时表达研究表明，与野生型相比，突变型cDNA产生的培养基蛋白量相似，但未检测到LCAT活性。该错义突变可能导致接近天然的构象，对细胞分泌影响不大，但产生催化缺陷的蛋白质。因此，除了Gly179至Gly183的催化活性共有序列以及Glu154至Lys173的假定固醇结合域外，N端结构域似乎对酶活性至关重要。
