Department of Internal Medicine, Division of Allergy and Immunology, Ege University Faculty of Medicine, Izmir, Turkey.
Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
Immunol Cell Biol. 2020 Sep;98(8):693-699. doi: 10.1111/imcb.12362. Epub 2020 Jul 12.
Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in the SERPING1 gene. Homozygosity for SERPING1 pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. In this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed to SERPING1 variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients.
遗传性血管性水肿是由于 C1 抑制剂（HAE-C1INH；MIM#106100）缺乏引起的一种罕见的常染色体疾病，受影响的个体通常为 SERPING1 基因中显性负变异的杂合子。同种合子性 SERPING1 致病变异体曾被认为是胚胎致死的；然而，在过去十年中已经描述了五个具有隐性 HAE 模式的非相关家族。在本报告中，我们对两个新报道的非相关、近亲繁殖的家族进行了功能特征分析，这些家族的 HAE 表现为 SERPING1 变体位于反应中心环（家族 D；S438F）和门（家族 A；I379T）区域。S438F 杂合子（家族 D）表现出 C1INH 完整的 105kDa 和切割/无活性的 96kDa 同工型的可变水平，而其纯合子相对物仅呈现 96kDa 带。功能研究表明，S438F 降低了 C1INH 与靶蛋白酶的相互作用，在杂合子（C1s，32-38%的对照和 FXIIa，28-35%的对照）和纯合子（C1s，18-24%的对照和 FXIIa，4-8%的对照）携带者中，这与家族中 HAE 更严重的表现和纯合子患者中 C1q 水平降低一致。相比之下，I379T 杂合子（家族 A）的血浆 C1INH 显示出正常的 C1INH/C1s 结合（84-94%的对照），并且 C1INH/FXIIa 复合物没有显著减少（50-70%的对照）。然而，纯合子不能抑制 C1s（25-42%的对照）和 FXIIa（14-18%的对照）。这种谱与家族中 HAE 较轻的表现以及杂合子和纯合子患者中 C4 和 C1q 水平的保守一致。
