Buonuomo Paola Sabrina, Bartuli Andrea, Rabacchi Claudio, Bertolini Stefano, Calandra Sebastiano
Rare Diseases and Medical Genetics, Bambino Gesù Children Hospital, Rome, Italy.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
J Clin Lipidol. 2015 Mar-Apr;9(2):265-70. doi: 10.1016/j.jacl.2014.10.003. Epub 2014 Oct 13.
Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL).
We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia.
A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging.
GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene.
家族性乳糜微粒血症是富含甘油三酯（TG）的脂蛋白血管内脂解的一种遗传缺陷。血管内脂解涉及TG水解酶脂蛋白脂肪酶（LPL）以及其他因素，如载脂蛋白CII和载脂蛋白AV（LPL的激活剂）、GPIHBP1（LPL在内皮表面发挥活性所需的分子平台）和LMF1（细胞内活性LPL形成所需的一个因子）。
我们对一名患有乳糜微粒血症的新生儿的家族性乳糜微粒血症候选基因进行了测序。
一名3日龄新生儿被发现患有乳糜微粒血症（血浆TG 18.8 mmol/L，1.667 mg/dL）。停止母乳喂养24小时后，血浆TG降至2.3 mmol/L（201 mg/dL），而恢复母乳喂养则导致TG急剧升高（7.9 mmol/L，690 mg/dL）。该患儿改为低脂饮食，在生命的头几个月里有效地将TG水平维持在3.5 mmol/L（294 mg/dL）以下。发现该患儿是GPIHBP1基因2个新突变的复合杂合子。第一个突变是外显子2中的9个碱基缺失和4个碱基插入，导致移码，消除了典型的终止密码子TGA。突变信使RNA的预测翻译产物是一种肽，包含野生型蛋白N末端的51个氨基酸，后面跟着252个新氨基酸。第二个突变是一个核苷酸变化（c.319T>C），导致氨基酸替代p.(Ser107Pro)，计算机模拟预测该替代具有损害性。
对于LPL基因无突变的乳糜微粒血症新生儿，应考虑GPIHBP1突变。
