Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia
Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia
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DOI：
10.1194/jlr.m002717
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发表时间：
2010-06-01
影响因子：
6.5
通讯作者：
Hernell, Olle
中科院分区：
文献类型：
--
作者：
Olivecrona, Gunilla;Ehrenborg, Ewa;Hernell, Olle
我们调查了一个来自瑞典北部的家庭，其中四个兄弟姐妹中有三个患有先天性乳糜微粒血症。肝素前后血浆中LPL活性和质量较低，注射肝素后LPL向血浆释放延迟。脂肪组织活检显示LPL活性和肿块正常。[S-35]对脂肪组织的蛋氨酸掺入研究表明，新合成的LPL大小正常，糖基化正常。受影响女性受试者的母乳中LPL质量和活动水平正常至升高。乳脂含量低于正常水平，脂肪酸组成与来自新生脂肪生成的乳脂相适应，而不是来自血浆脂蛋白。考虑到LPL在肝素后延迟释放到血浆中，我们怀疑乳糜微粒血症可能是由GPIHBP1突变引起的。事实上，所有三个受影响的兄弟姐妹都是GPIHBP1 (C65S和C68G) Ly6结构域高度保守的半胱氨酸错义突变的复合杂合子。突变的GPIHBP1蛋白到达了转染的中国仓鼠卵巢细胞的表面，但其结合LPL的能力存在缺陷（通过基于细胞和无细胞的LPL结合试验来判断）。因此，Ly6结构域的保守半胱氨酸对GPIHBP1的功能至关重要。-Olivecrona， G.、E. Ehrenborg、H. Semb、E. Makoveichuk、A. Lindberg、M. R. Hayden、P. Gin、B. S. J. Davies、M. M. Weinstein、L. G. Fong、A. P. Beigneux、S. G. Young、T. Olivecrona和O. Hernell。家族性乳糜低血症患者GPIHBP1 Ly6结构域保守半胱氨酸突变。[j] .油脂杂志。2010。51: 1535 - 1545。
We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. LPL activity and mass in pre- and postheparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. [S-35] Methionine incorporation studies on adipose tissue showed that newly synthesized LPL was normal in size and normally glycosylated. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids being derived from de novo lipogenesis, rather than from the plasma lipoproteins. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1. Indeed, all three affected siblings were compound heterozygotes for missense mutations involving highly conserved cysteines in the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1 proteins reached the surface of transfected Chinese hamster ovary cells but were defective in their ability to bind LPL (as judged by both cell-based and cell-free LPL binding assays). Thus, the conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function.-Olivecrona, G., E. Ehrenborg, H. Semb, E. Makoveichuk, A. Lindberg, M. R. Hayden, P. Gin, B. S. J. Davies, M. M. Weinstein, L. G. Fong, A. P. Beigneux, S. G. Young, T. Olivecrona, and O. Hernell. Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. J. Lipid Res. 2010. 51: 1535-1545.