Cox L A, Jett C, Hixson J E
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245, USA.
J Lipid Res. 1998 Jul;39(7):1319-26.
Apolipoprotein[a] (apo[a]), a unique component of atherogenic lipoprotein[a], is highly polymorphic in human and nonhuman primates. Null alleles, producing no detectable circulating Lp[a] or apo[a] isoforms, are found at high frequencies. The molecular basis of null alleles is not yet known. In baboons, approximately two-thirds of null alleles do not produce detectable hepatic transcripts (transcript negative nulls), and one-third of null alleles produce normal amounts of apo[a] transcripts (transcript positive nulls). We have cloned apo[a] cDNA from a baboon carrying a transcript positive null allele defective in secretion from primary hepatocytes. Compared with wild-type cDNA, the null allele contained an in-frame 47 amino acid deletion in the protease domain corresponding to one exon of the apo[a] gene. The null allele contains an A-->T substitution in the third nucleotide position of the intron downstream of the deleted exon which alters the donor splice site consensus sequence. Thus, this null is likely due to a mutation that prevents normal mRNA splicing, yielding a shortened protein that may be defective in intramolecular interactions required for normal processing and secretion of apo[a]. This is the first report of a molecular basis for apo[a] null alleles.
载脂蛋白[a]（apo[a]）是致动脉粥样硬化脂蛋白[a]的独特成分，在人类和非人类灵长类动物中具有高度多态性。在高频率下可发现不产生可检测循环Lp[a]或apo[a]异构体的无效等位基因。无效等位基因的分子基础尚不清楚。在狒狒中，大约三分之二的无效等位基因不产生可检测的肝脏转录本（转录本阴性无效等位基因），三分之一的无效等位基因产生正常量的apo[a]转录本（转录本阳性无效等位基因）。我们从一只携带转录本阳性无效等位基因且原代肝细胞分泌存在缺陷的狒狒中克隆了apo[a] cDNA。与野生型cDNA相比，无效等位基因在蛋白酶结构域中存在一个对应于apo[a]基因一个外显子的框内47个氨基酸的缺失。无效等位基因在缺失外显子下游内含子的第三个核苷酸位置存在A→T替换，这改变了供体剪接位点共有序列。因此，这种无效等位基因可能是由于一种突变导致正常mRNA剪接受阻，产生一种缩短的蛋白质，该蛋白质可能在apo[a]正常加工和分泌所需的分子内相互作用中存在缺陷。这是关于apo[a]无效等位基因分子基础的首次报道。
