Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.
Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.
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DOI：
10.1161/atvbaha.109.186577
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发表时间：
2009-06
期刊：
影响因子：
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通讯作者：
Young SG
中科院分区：
文献类型：
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作者：
Beigneux AP;Franssen R;Bensadoun A;Gin P;Melford K;Peter J;Walzem RL;Weinstein MM;Davies BS;Kuivenhoven JA;Kastelein JJ;Fong LG;Dallinga-Thie GM;Young SG
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，因此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。对患有严重高甘油三酯血症的患者（n=60，血浆甘油三酯高于年龄和性别的第 95 个百分位）进行了 GPIHBP1 突变筛查。在一名患有终生乳糜微粒血症的 33 岁男性中发现了纯合 GPIHBP1 突变 (c.344A>C)，该突变将残基 115 处高度保守的谷氨酰胺改变为脯氨酸 (p.Q115P)。该患者小时候发育不良，但没有胰腺炎病史。他的 LPL、APOA5 或 APOC2 没有突变。 Q115P 取代不影响 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 也无法结合 LPL。在一名乳糜微粒血症患者中发现了 GPIHBP1 (Q115P) 纯合错义突变。该突变消除了 GPIHBP1 结合 LPL 和乳糜微粒的能力，强烈表明它导致了患者的乳糜微粒血症。
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.