Perlmutter D H
Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583, USA.
Cell Death Differ. 2009 Jan;16(1):39-45. doi: 10.1038/cdd.2008.103. Epub 2008 Jul 11.
Alpha-1-antitrypsin (AT) deficiency is a relatively common autosomal co-dominant disorder, which causes chronic lung and liver disease. A point mutation renders aggregation-prone properties on a hepatic secretory protein in such a way that the mutant protein is retained in the endoplasmic reticulum of hepatocytes rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows neutrophil proteases to degrade the connective tissue matrix of the lung causing chronic emphysema. Accumulation of aggregated mutant AT in the endoplasmic reticulum of hepatocytes causes liver inflammation and carcinogenesis by a gain-of-toxic function mechanism. However, genetic epidemiology studies indicate that many, if not the majority of, affected homozygotes are protected from liver disease by unlinked genetic and/or environmental modifiers. Studies performed over the last several years have demonstrated the importance of autophagy in disposal of mutant, aggregated AT and raise the possibility that predisposition to, or protection from, liver injury and carcinogenesis is determined by the balance of de novo biogenesis of the mutant AT molecule and its autophagic disposal.
α1抗胰蛋白酶（AT）缺乏症是一种相对常见的常染色体共显性疾病，可导致慢性肺和肝脏疾病。一个点突变使一种肝脏分泌蛋白具有易于聚集的特性，导致突变蛋白保留在肝细胞的内质网中，而不是分泌到血液和体液中，它通常在血液和体液中作为中性粒细胞蛋白酶的抑制剂发挥作用。功能丧失机制使中性粒细胞蛋白酶降解肺的结缔组织基质，导致慢性肺气肿。聚集的突变型AT在肝细胞内质网中的积累通过获得毒性功能机制导致肝脏炎症和致癌作用。然而，遗传流行病学研究表明，许多（如果不是大多数）受影响的纯合子通过不连锁的遗传和/或环境修饰因子免受肝脏疾病的影响。过去几年进行的研究表明自噬在处理突变的、聚集的AT中的重要性，并提出易患或免受肝损伤和致癌作用可能由突变型AT分子的从头生物合成与其自噬处理之间的平衡决定。
