Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes.
Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes.
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DOI：
10.1172/jci116551
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发表时间：
1993-07
期刊：
影响因子：
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通讯作者：
D. E. Wilson;A. Hata;L. Kwong;A. Lingam;J. Shuhua;D. Ridinger;C. Yeager;K. C. Kaltenborn;P. Iverius;J. Lalouel
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文献类型：
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作者：
D. E. Wilson;A. Hata;L. Kwong;A. Lingam;J. Shuhua;D. Ridinger;C. Yeager;K. C. Kaltenborn;P. Iverius;J. Lalouel
患有乳糜粒微粒血症、胰腺炎和非胰岛素依赖型糖尿病(NIDDM)的先证者在脂蛋白脂酶(LPL)基因外显子3上有两种不同的突变：75Arg-->；Ser错义突变，通过父系遗传；73Tyr-->；Ter，通过母系遗传。NIDDM似乎是独立分离的。对R75S突变体在COS-1细胞提取液和培养液中的表达进行了研究。可检测到的具有催化活性的R75S LPL的量表明，与外显子5突变一样，活性同源二聚体不稳定(Hata等人。1992年。J.Biol.化学。267：20132-20139)。短链脂肪酸酯的水解表明，R75S不直接影响apoC-II对LPL的激活。患有NIDDM和野生型LPL的受试者以及73Tyr--&Gt；Ter截短的非糖尿病中年携带者有中等程度的高甘油三酯血症(260-521 mg/dl)和降低的高密度脂蛋白胆固醇。一位患有NIDDM的阿姨接受了截肢手术。她的表型(甘油三酯5,300 mg/dl，发作性黄瘤和复发性胰腺炎)与纯合子或复合杂合子一样严重。我们的结论是：(A)携带LPL基因功能障碍的糖尿病携带者有发生严重血脂的风险；(B)NIDDM的生理缺陷可能是与LPL杂合性缺陷相加或协同作用的。
A proband with chylomicronemia, pancreatitis, and non-insulin-dependent diabetes (NIDDM) bears two different mutations in exon 3 of the lipoprotein lipase (LPL) gene: a missense mutation, 75Arg-->Ser, inherited through the paternal line and a truncation, 73Tyr-->Ter, through the maternal line. NIDDM appeared to be independently segregating. The R75S mutant was studied in extracts and media from transfected COS-1 cells. Detectable amounts of catalytically competent R75S LPL suggested destabilization of the active homodimer as with exon 5 mutants (Hata et al. 1992. J. Biol. Chem. 267:20132-20139). Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II. Subjects with NIDDM and wild-type LPL, and nondiabetic middle-aged carriers of the 73Tyr-->Ter truncation had moderate hypertriglyceridemia (260-521 mg/dl) and reduced high density lipoprotein cholesterol. A maternal aunt with NIDDM carried the truncation. Her phenotype (triglycerides of 5,300 mg/dl, eruptive xanthomatosis, and recurrent pancreatitis) was as severe as that in homozygotes or compound heterozygotes. We conclude: (a) diabetic carriers of dysfunctional LPL alleles are at risk for severe lipemia; and (b) the physiologic defects in NIDDM may be additive or synergistic with heterozygous LPL deficiency.