Franssen Remco, Young Stephen G, Peelman Frank, Hertecant Jozef, Sierts Jeroen A, Schimmel Alinda W M, Bensadoun André, Kastelein John J P, Fong Loren G, Dallinga-Thie Geesje M, Beigneux Anne P
Department of Vascular Medicine, Academic Medical Center Amsterdam, The Netherlands.
Circ Cardiovasc Genet. 2010 Apr;3(2):169-78. doi: 10.1161/CIRCGENETICS.109.908905. Epub 2010 Feb 2.
Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins.
We report the discovery of a homozygous missense mutation in GPIHBP1 in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL.
We identified a novel GPIHBP1 missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans.
最近在小鼠中的研究证实，一种内皮细胞蛋白，即糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白1（GPIHBP1），对于富含甘油三酯的脂蛋白的脂解过程至关重要。
我们报告了在一名患有严重乳糜微粒血症的小男孩中发现GPIHBP1存在纯合错义突变。该突变，即p.C65Y，用酪氨酸取代了GPIHBP1淋巴细胞抗原6结构域中一个保守的半胱氨酸，预计会通过干扰二硫键的形成来扰乱蛋白质结构。对转染的中国仓鼠卵巢细胞的研究表明，GPIHBP1-C65Y能够到达细胞表面，但失去了结合脂蛋白脂肪酶（LPL）的能力。当给GPIHBP1-C65Y纯合子静脉推注肝素时，只有微量的LPL进入血浆。我们还观察到一名患有乳糜微粒血症且为另一种GPIHBP1突变（p.Q115P）纯合子的受试者在注射肝素后的血浆中LPL水平非常低。当给GPIHBP1-Q115P纯合子输注6小时肝素时，血浆中出现了大量的LPL，导致血浆甘油三酯水平从1780降至120 mg/dL。
我们在一名患有严重乳糜微粒血症的小男孩中鉴定出一种与LPL结合缺陷相关的新型GPIHBP1错义突变（p.C65Y）。我们还表明，C65Y或Q115P突变的纯合性与注射肝素后血浆中LPL水平低有关，这表明GPIHBP1对人类血浆甘油三酯代谢很重要。
