Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
J Allergy Clin Immunol. 2018 Mar;141(3):1009-1017. doi: 10.1016/j.jaci.2017.05.020. Epub 2017 Jun 8.
Hereditary angioedema (HAE) is a rare genetic disease usually caused by mutation in the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE, no causative variants have been described, and the pathophysiology of the disease remains unknown (hereditary angioedema with yet unknown genetic defect [U-HAE]). Identification of causative genes in patients with U-HAE is valuable for understanding the cause of the disease.
We conducted genetic studies in Italian patients with U-HAE to identify novel causative genes.
Among patients belonging to 10 independent families and unrelated index patients with U-HAE recruited from the Italian Network for C1-INH-HAE (ITACA), we selected a large multiplex family with U-HAE and performed whole-exome sequencing. The angiopoietin-1 gene (ANGPT1) was investigated in all patients with familial or sporadic U-HAE. The effect of ANGPT1 variants was investigated by using in silico prediction and plasma and transfected cells from both patients and control subjects.
We identified a missense mutation (ANGPT1, c.807G>T, p.A119S) in a family with U-HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U-HAE but not in asymptomatic family members or an additional 20 patients with familial U-HAE, 22 patients with sporadic U-HAE, and 200 control subjects. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor tunica interna endothelial cell kinase 2 of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed reduced binding capability to its receptor.
ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.
遗传性血管性水肿（HAE）是一种罕见的遗传性疾病，通常由 C1 抑制剂或凝血因子 XII 基因突变引起。然而，在一系列 HAE 患者中，尚未描述致病变异，疾病的病理生理学仍不清楚（遗传性血管性水肿，未知遗传缺陷[U-HAE]）。在 U-HAE 患者中鉴定致病基因对于了解疾病的病因具有重要意义。
我们对意大利 U-HAE 患者进行了遗传研究，以鉴定新的致病基因。
在意大利 C1-INH-HAE 网络（ITACA）招募的 10 个独立家族的患者和无关联的 U-HAE 索引患者中，我们选择了一个具有 U-HAE 的大型多态性家族，并进行了全外显子组测序。对所有具有家族性或散发性 U-HAE 的患者进行了血管生成素 1 基因（ANGPT1）的研究。通过使用计算机预测和来自患者和对照的血浆和转染细胞来研究 ANGPT1 变体的影响。
我们在一个具有 U-HAE 的家族中发现了一个错义突变（ANGPT1，c.807G>T，p.A119S）。ANGPT1 p.A119S 变体在 U-HAE 指数家族的所有成员中均有检测到，但在无症状的家族成员或另外 20 名家族性 U-HAE 患者、22 名散发性 U-HAE 患者和 200 名对照中均未检测到。对患者血浆的蛋白分析显示，ANGPT1 p.A119S 变体的多聚体形式减少，与天然受体血管内皮层激酶 2 的结合能力降低。重组突变的 ANGPT1 p.A119S 形成的多聚体数量减少，与受体的结合能力降低。
ANGPT1 功能障碍与血管性水肿有关，ANGPT1 变体可能是 HAE 的基础。
