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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >A newly identified lipoprotein lipase (LPL) gene mutation (F270L) in a Japanese patient with familial LPL deficiency
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A newly identified lipoprotein lipase (LPL) gene mutation (F270L) in a Japanese patient with familial LPL deficiency

机译：一个新发现的脂蛋白脂肪酶（LPL）基因突变（F270L）在日本家族性LPL缺乏症患者中

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摘要

We have systematically investigated the molecular defects resulting in a primary lipoprotein lipase (LPL) deficiency in a Japanese male infant (proband SH) with fasting hyperchylomicronemia. Neither LPL activity nor immunoreactive LPL mass was detected in pre- or postheparin plasma from proband SH. DNA sequence analysis of the LPL gene of proband SH revealed homozygoisty for a novel missense mutation of F270L (Phe~(270) → Leu/TTT~(1065) → TTG) in exon 6. The function of the mutant F270L LPL was determined by both biochemical and immunocytochemical studies. In vitro expression experiments on the mutant F270L LPL cDNA in COS-1 cells demonstrated that the mutant LPL protein was synthesized as a catalytically inactive form and its total amount was almost equal to that of the normal LPL. Moreover, the synthesized mutant LPL was non-releasable by heparin because the intracellular transport of the mutant LPL to the cell surface - by which normal LPL becomes heparin-releasable - was impaired due to the abnormal structure of the mutant LPL protein. These findings explain the failure to detect LPL activities and masses in pre- and postheparin plasma of the proband. The mutant F270L allele generated an XcmI restriction enzyme site in exon 6 of the LPL gene. The carrier status of F270L in the proband's family members was examined by digestion with XcmI. The proband was ascertained to be homozygous for the F270L mutation and his parents and sister were all heterozygous. The LPL activities and masses of the parents and the sister (carriers) were half or less than half of the control values. Regarding the phenotype of the carriers, the mother with a sign of hyperinsulinemia manifested hypertriglyceridemia (type IV hyperlipoproteinemia), whereas the healthy father and the sister were normolipidemic. Hyperinsulinemia may be a strong determinant of hypertriglyceridemia in subjects with heterozygous LPL deficiency.
机译：我们已经系统地研究了空腹高乳糜血症的日本男婴（先证者SH）中导致主要脂蛋白脂肪酶（LPL）缺乏的分子缺陷。在先证者SH的肝素之前或之后血浆中均未检测到LPL活性或免疫反应性LPL质量。先证者SH的LPL基因的DNA序列分析揭示了外显子6中F270L的新型错义突变（Phe〜（270）→Leu / TTT〜（1065）→TTG）的纯合子。突变体F270L LPL的功能由生化和免疫细胞化学研究。在COS-1细胞中对突变的F270L LPL cDNA进行的体外表达实验表明，该突变的LPL蛋白以催化失活形式合成，其总量几乎与正常LPL相等。此外，合成的突变体LPL不可被肝素释放，因为由于突变体LPL蛋白的异常结构，突变体LPL向细胞表面的细胞内运输（正常的LPL可通过肝素可释放）受到损害。这些发现解释了无法检测先证者肝素前后血浆中的LPL活性和质量。突变的F270L等位基因在LPL基因的外显子6中产生XcmI限制性酶切位点。通过XcmI消化检查了先证者家庭成员中F270L的携带者状况。确定该先证者对于F270L突变是纯合的，并且他的父母和妹妹都是杂合的。父母和姐妹（携带者）的LPL活动和质量为对照值的一半或不到一半。关于携带者的表型，有高胰岛素血症迹象的母亲表现出高甘油三酸酯血症（IV型高脂蛋白血症），而健康的父亲和妹妹则血脂正常。高胰岛素血症可能是LPL缺乏症杂合症患者高甘油三酯血症的重要决定因素。

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