PDF(Pubmed)
Abstract：
Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant\'s effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.
摘要：
背景：遗传性血管性水肿（HAE）是一种严重且可能危及生命的疾病。最常见的形式是由SERPING1的变体引起的，导致C1抑制剂（C1-INH）缺乏（HAE-C1-INH）。C1-INH是一种丝氨酸蛋白酶抑制剂（SERPIN），可调节多种蛋白酶途径，包括激肽释放酶-激肽系统（KKS）及其补充。在HAE-C1-INH患者中，C1-INH缺乏影响KKS控制，导致血浆中激肽释放酶活性的发展和随后的缓激肽（BK）的释放。虽然绝大多数引起疾病的SERPING1变体是显性的，很少有隐性变异被描述。我们提出了一个大型的巴西HAE-C1-INH家族，具有HAE-C1-INH的隐性形式。方法：对家庭成员的血液样本进行C1-INH的蛋白质水平调查，C4,C1q,和C1-INH功能。对SERPING1基因进行测序。结果：在两个受影响严重的姐妹中，我们在SERPING1中鉴定了纯合错义变体（NM_000062.3：c.964G>A；p。Val322Met）。14个家族成员是该变异体的无症状杂合携带者。关于血浆中C1-INH功能的数据显示纯合p.Val322Met强烈影响C1-INH功能以抑制Cls和激肽释放酶(PKa)。当杂合表达时，与PKa相比，它对C1-INH控制的影响更大。结论：这些关于变体对结构-功能关系的影响的研究加强了先前的观察，表明C1-INH缺乏是一种构象疾病。
