Dewald Georg
Institute for Molecular and Preventive Medicine, Kurfürstenstr. 10, 56068 Koblenz, Germany.
Biochem Biophys Res Commun. 2018 Mar 25;498(1):193-198. doi: 10.1016/j.bbrc.2017.12.060.
Hereditary angioedema (HAE) is a genetically heterogeneous disease that is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The two classic types, HAE types I and II, are both caused by mutations in the complement C1 inhibitor (SERPING1) gene resulting either in a quantitative or a qualitative deficiency of C1 inhibitor. In so-called HAE type III, in contrast, patients show normal C1 inhibitor measurements in plasma ('HAE with normal C1 inhibitor'). As previously shown by us, one subgroup of 'HAE with normal C1 inhibitor' is caused by mutations of the coagulation factor XII (F12) gene. For the present study, following the exclusion of numerous candidate genes, we screened eight unrelated index patients representing eight 'HAE families with normal C1 inhibitor and no F12 mutation' for mutations in the plasminogen (PLG) gene. A rare non-conservative missense mutation was newly identified in exon 9 of the PLG gene. This mutation (c.1100A > G), encountered in three out of eight patients, predicts a lysine-to-glutamic acid substitution in position 311 of the mature protein (p.Lys311Glu). Using isoelectric focusing of plasma samples followed by an immunoblotting procedure we demonstrated that the presence of the mutation is associated with a dysplasminogenemia, namely the presence of an aberrant plasminogen protein. The predicted structural and functional impact of the mutation, its absence in 139 control individuals, and its co-segregation with the phenotype in three large families provide strong support that it causes disease. Extending a previously proposed gene-based alphabetic nomenclature for the various HAE types one may use the term 'HAE type C' for the HAE entity described here.
遗传性血管性水肿（HAE）是一种基因异质性疾病，其特征为反复出现皮肤肿胀、腹痛发作以及可能危及生命的上呼吸道梗阻。两种经典类型，即HAE I型和II型，均由补体C1抑制因子（SERPING1）基因突变引起，导致C1抑制因子出现定量或定性缺陷。相比之下，在所谓的HAE III型中，患者血浆中C1抑制因子检测值正常（“C1抑制因子正常的HAE”）。正如我们之前所表明的，“C1抑制因子正常的HAE”的一个亚组是由凝血因子XII（F12）基因突变引起的。在本研究中，在排除众多候选基因后，我们对代表八个“C1抑制因子正常且无F12突变的HAE家族”的八名无关索引患者进行了纤溶酶原（PLG）基因突变筛查。在PLG基因的外显子9中新发现了一种罕见的非保守错义突变。该突变（c.1100A > G）在八名患者中的三名中出现，预测成熟蛋白第311位的赖氨酸被谷氨酸取代（p.Lys311Glu）。通过对血浆样本进行等电聚焦，随后进行免疫印迹程序，我们证明该突变的存在与异常纤溶酶原血症相关，即存在异常的纤溶酶原蛋白。该突变预测的结构和功能影响、在139名对照个体中未出现以及在三个大家系中与表型的共分离，都有力支持了它导致疾病这一结论。扩展先前提出的针对各种HAE类型基于基因的字母命名法，对于此处描述的HAE实体，人们可以使用“HAE C型”这一术语。
