Seixas Susana, Marques Patricia Isabel
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
Appl Clin Genet. 2021 Mar 22;14:173-194. doi: 10.2147/TACG.S257511. eCollection 2021.
Alpha-1-Antitrypsin deficiency (AATD), caused by mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p.Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare variants (>500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss- or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.
α-1抗胰蛋白酶缺乏症（AATD）由基因突变引起，是欧洲血统个体中最常见的孟德尔疾病之一。然而，这种疾病的特征是血清α-1抗胰蛋白酶（AAT）水平降低，并且在儿童和成人中都与肺气肿和肝病风险增加相关，仍然经常被漏诊。AATD的临床表现通常与两种致病变体相关，即Z等位基因（p.Glu342Lys）和S等位基因（p.Glu264Val），它们可以组合成严重的ZZ或中度的SZ风险基因型。然而，对AATD病例的筛查以及在对照人群和疾病人群中进行的大规模测序工作发现了大量罕见变体（>500种），包括许多致病和其他可能有害的突变。一般来说，致病变体可根据其病理生理效应分为功能丧失或功能获得。在AATD中，功能丧失与天然抑制剂AAT对弹性蛋白酶的失控活性相关。这种现象可能是由于缺乏循环AAT（无效等位基因）、肝细胞AAT分泌不良（缺陷等位基因）甚至是由于抑制活性改变（功能失调等位基因）导致的。另一方面，功能获得与AAT聚合物的形成及其对细胞应激和炎症反应的开启有关（缺陷等位基因）。较少见的是，功能获得与蛋白酶亲和力改变有关（功能失调等位基因）。在这里，我们重新审视突变谱、其起源和群体历史，更加强调符合AATD发病机制上述过程的变体。这些变体是根据其临床意义和更广泛的地理分布选择的。此外，我们还为未来AATD临床异质性和综合诊断的研究提供了一些方向。
