A naturally occurring nonpolymerogenic mutant of α1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum
A naturally occurring nonpolymerogenic mutant of α1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum
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DOI：
10.1074/jbc.m105226200
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发表时间：
2001-09-07
影响因子：
4.8
通讯作者：
Perlmutter, DH
中科院分区：
文献类型：
--
作者：
Lin, L;Schmidt, B;Perlmutter, DH
经典形式的α 1-抗胰蛋白酶（α 1-AT）缺乏症与在肝细胞内质网（ER）中聚合的突变α 1-ATZ分子有关。蛋白酶抑制剂（PI）Z等位基因纯合子的一个亚组个体发生慢性肝损伤并易患肝细胞癌。在这项研究中，我们评估了一个家庭，其中三个受影响的成员有严重的肝脏疾病与β-AT缺乏症的β-AT的一级结构。我们发现，一个同胞是一个复合杂合子，具有一个PI Z等位基因和第二个等位基因，PI Z + saar等位基因，携带突变的特点，ATZ以及突变的特点，ATSaarbrucken（ATSaar）。Pl saar中的突变引入了提前终止密码子，导致在其羧基末端截短19个氨基酸的Mpal-AT蛋白。对患有严重肝病的第二个同胞和其他活着的家庭成员的研究没有揭示出存在的α-AT saar突变，因此没有证实该突变在该家族的肝病表型中的作用。然而，在异源细胞中表达的p53 al-AT saar和p53 al-ATZ + saar的研究表明，这些突变体存在延长的细胞内保留，即使它们不具有聚合物生成特性。因此，这些结果具有重要的意义，进一步了解的命运的突变体martinal-AT分子，ER滞留的机制，和肝损伤的发病机制，在martinal-AT缺乏。
The classical form of alphal-antitrypsin (alphal-AT) deficiency is associated with a mutant alpha1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of alphal-AT in a family in which three affected members had severe liver disease associated with alphal-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes alphal-ATZ as well as the mutation that characterizes alphal-AT Saarbrucken (alphal-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an alphal-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the alphal-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of alphal-AT saar and alphal-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant alphal-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alphal-AT deficiency.