Henderson H E, Ma Y, Hassan M F, Monsalve M V, Marais A D, Winkler F, Gubernator K, Peterson J, Brunzell J D, Hayden M R
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
J Clin Invest. 1991 Jun;87(6):2005-11. doi: 10.1172/JCI115229.
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.
脂蛋白脂肪酶（LPL）缺乏症的分子生物学研究因LPL基因探针的可得性以及人类LPL缺乏症潜在基因突变的近期特征描述而得到推动。通常，错义突变占主导，且优先定位于外显子4和5。这种分布支持了早期研究将功能重要性归因于这些外显子编码的残基。我们现在报告在三名无亲缘关系的患者中LPL基因外显子5内又发现了一个错义突变。通过聚合酶链反应对单个外显子进行扩增并直接测序，发现在LPL cDNA的第194密码子处发生了T----C转换，导致该残基处的异亮氨酸被苏氨酸取代。通过在COS-1细胞中的体外诱变研究证实了该突变诱导的催化异常。用含有第194密码子转换的LPL cDNA进行转染导致合成并分泌了一种催化缺陷的蛋白质。苏氨酸194取代与两种不同的DNA单倍型相关，这与该突变的多中心起源一致。
