Crowther Damian C, Belorgey Didier, Miranda Elena, Kinghorn Kerri J, Sharp Lynda K, Lomas David A
1Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK.
Eur J Hum Genet. 2004 Mar;12(3):167-72. doi: 10.1038/sj.ejhg.5201127.
Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies.
α1-抗胰蛋白酶（α1-antitrypsin）是丝氨酸蛋白酶抑制剂或丝氨酸蛋白酶抑制因子（serpin）超家族的典型成员。最常见的严重缺陷变体是Z等位基因，它会导致突变蛋白在肝细胞内蓄积。这种“蛋白质过载”会引发新生儿肝炎、肝硬化和肝细胞癌。循环血浆中α1-抗胰蛋白酶的缺乏会导致早发性全小叶型肺气肿。Zα1-抗胰蛋白酶缺乏的潜在机制是由于蛋白质内异常的构象转变以及聚合物链的形成，这些聚合物链在肝细胞的分泌途径中缠结。这种机制也是丝氨酸蛋白酶抑制因子超家族其他成员血浆缺乏的基础，从而导致一类称为丝氨酸蛋白酶抑制因子病的疾病。具体而言，已报道抗凝血酶、C1抑制因子和α1-抗糜蛋白酶的突变等位基因有利于聚合物的自发形成以及蛋白质在肝细胞内的潴留。随之而来的血浆中抗凝血酶、C1抑制因子和α1-抗糜蛋白酶的缺乏分别导致血栓形成、血管性水肿和肺气肿。此外，神经丝氨酸蛋白酶突变体的聚合导致聚合物在神经元内潴留，从而引发包涵体痴呆、伴有神经丝氨酸蛋白酶包涵体的家族性脑病或FENIB。我们在此综述α1-抗胰蛋白酶缺乏的遗传和分子基础及临床特征，并展示其如何为理解其他丝氨酸蛋白酶抑制因子病提供一个平台。
