Beigneux Anne P, Franssen Remco, Bensadoun André, Gin Peter, Melford Kristan, Peter Jorge, Walzem Rosemary L, Weinstein Michael M, Davies Brandon S J, Kuivenhoven Jan A, Kastelein John J P, Fong Loren G, Dallinga-Thie Geesje M, Young Stephen G
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):956-62. doi: 10.1161/ATVBAHA.109.186577. Epub 2009 Mar 19.
GPIHBP1 is an endothelial cell protein that binds lipoprotein lipase (LPL) and chylomicrons. Because GPIHBP1 deficiency causes chylomicronemia in mice, we sought to determine whether some cases of chylomicronemia in humans could be attributable to defective GPIHBP1 proteins.
Patients with severe hypertriglyceridemia (n=60, with plasma triglycerides above the 95th percentile for age and gender) were screened for mutations in GPIHBP1. A homozygous GPIHBP1 mutation (c.344A>C) that changed a highly conserved glutamine at residue 115 to a proline (p.Q115P) was identified in a 33-year-old male with lifelong chylomicronemia. The patient had failure-to-thrive as a child but had no history of pancreatitis. He had no mutations in LPL, APOA5, or APOC2. The Q115P substitution did not affect the ability of GPIHBP1 to reach the cell surface. However, unlike wild-type GPIHBP1, GPIHBP1-Q115P lacked the ability to bind LPL or chylomicrons (d < 1.006 g/mL lipoproteins from Gpihbp1(-/-) mice). Mouse GPIHBP1 with the corresponding mutation (Q114P) also could not bind LPL.
A homozygous missense mutation in GPIHBP1 (Q115P) was identified in a patient with chylomicronemia. The mutation eliminated the ability of GPIHBP1 to bind LPL and chylomicrons, strongly suggesting that it caused the patient's chylomicronemia.
GPIHBP1是一种内皮细胞蛋白，可结合脂蛋白脂肪酶（LPL）和乳糜微粒。由于GPIHBP1缺乏会导致小鼠出现乳糜微粒血症，我们试图确定人类的某些乳糜微粒血症病例是否可归因于GPIHBP1蛋白缺陷。
对严重高甘油三酯血症患者（n = 60，血浆甘油三酯高于年龄和性别的第95百分位数）进行GPIHBP1突变筛查。在一名患有终身乳糜微粒血症的33岁男性中发现了一个纯合的GPIHBP1突变（c.344A>C），该突变将第115位残基处高度保守的谷氨酰胺变为脯氨酸（p.Q115P）。该患者小时候生长发育迟缓，但无胰腺炎病史。他的LPL、APOA5或APOC2没有突变。Q115P替代并不影响GPIHBP1到达细胞表面的能力。然而，与野生型GPIHBP1不同，GPIHBP1 - Q115P缺乏结合LPL或乳糜微粒的能力（来自Gpihbp1(-/-)小鼠的d < 1.006 g/mL脂蛋白）。具有相应突变（Q114P）的小鼠GPIHBP1也不能结合LPL。
在一名乳糜微粒血症患者中鉴定出GPIHBP1的纯合错义突变（Q115P）。该突变消除了GPIHBP1结合LPL和乳糜微粒的能力，强烈提示它导致了患者的乳糜微粒血症。
