AMINO-ACID SUBSTITUTION (ILE194-]THR) IN EXON-5 OF THE LIPOPROTEIN-LIPASE GENE CAUSES LIPOPROTEIN-LIPASE DEFICIENCY IN 3 UNRELATED PROBANDS - SUPPORT FOR A MULTICENTRIC ORIGIN
AMINO-ACID SUBSTITUTION (ILE194-]THR) IN EXON-5 OF THE LIPOPROTEIN-LIPASE GENE CAUSES LIPOPROTEIN-LIPASE DEFICIENCY IN 3 UNRELATED PROBANDS - SUPPORT FOR A MULTICENTRIC ORIGIN
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DOI：
10.1172/jci115229
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发表时间：
1991-06-01
影响因子：
15.9
通讯作者：
HAYDEN, MR
中科院分区：
文献类型：
--
作者：
HENDERSON, HE;MA, Y;HAYDEN, MR
脂蛋白脂酶(LPL)基因探针的问世和人类LPL缺乏症相关基因突变的研究为LPL缺乏症的分子生物学研究提供了便利。通常情况下，错义突变占主导地位，并优先定位于外显子4和5。这种分布支持了早期将功能意义归因于这些外显子编码的残基的研究。我们现在报告在三个无关的患者中LPL基因外显子5内的进一步错义突变。通过聚合酶链式反应和直接测序对单个外显子进行扩增，发现LPL基因第194位密码子发生T-->；C转变，导致该残基上的苏氨酸取代异亮氨酸。通过对COS-1细胞的体外诱变研究，证实了该突变所致的催化异常。用含有第194位密码子转换的LPL基因的cDNAs，可以合成和分泌一种催化缺陷的蛋白质。Thr194替换与两种不同的DNA单倍型相关，与该突变的多中心起源一致。
Studies on the molecular biology of lipoprotein lipase (LPL) deficiency have been facilitated by the availability of LPL gene probes and the recent characterization of gene mutations underlying human LPL deficiency. Typically, missense mutations have predominated and show a preferential localization to exons 4 and 5. This distribution supports earlier studies attributing functional significance to residues encoded by these exons. We now report a further missense mutation within exon 5 of the LPL gene in three unrelated patients. Amplification of individual exons by the polymerase chain reaction and direct sequencing revealed a T --> C transition at codon 194 of the LPL cDNA which results in a substitution of threonine for isoleucine at this residue. The catalytic abnormality induced by this mutation was confirmed through in vitro mutagenesis studies in COS-1 cells. Transfection with a LPL cDNA containing the codon 194 transition resulted in the synthesis and secretion of a catalytically defective protein. The Thr194 substitution was associated with two different DNA haplotypes, consistent with a multicentric origin for this mutation.