A novel C1 inhibitor gene mutation in a family with hereditary angioedema: Use of genetic analysis to facilitate early diagnosis
A novel C1 inhibitor gene mutation in a family with hereditary angioedema: Use of genetic analysis to facilitate early diagnosis
复制标题
遗传性血管性水肿家族中的新型 C1 抑制剂基因突变：利用遗传分析促进早期诊断
DOI：
10.1016/j.alit.2019.07.005
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发表时间：
2020
影响因子：
6.8
通讯作者：
Yoshida A
中科院分区：
文献类型：
--
作者：
Yokoyama K;Horiuchi T;Hashimura C;Yoshida A
遗传性血管性水肿(HAE)是一种罕见的常染色体显性遗传性疾病，以反复发作的血管水肿或深部局限性肿胀为特征，无荨麻疹皮疹。HAE最常影响上呼吸道和胃肠道的皮肤或粘膜组织，喉部受累可能导致致命的窒息。在大多数情况下，HAE是由于SERPING1基因突变所致，SERPING1基因编码丝氨酸蛋白酶C1抑制物(C1-INH)；I型HAE是由C1-INH缺乏引起的，而II型是由C1-INH功能障碍引起的。在这里，我们报告了一个HAE I型家系，在SERPING1中携带一个新的错义突变。该研究方案得到了日本红十字会和歌山医疗中心机构审查委员会的批准(第548号)。患者6，男，31岁，在2年内出现两次肢体、嘴唇、面部、生殖器和腹部血管水肿，无呼吸道症状。他的第一集的导火索是在他快30岁的时候感染了手足口病，而第二集的导火索，发生在第一集的一年后，还不清楚。结肠纤维光镜检查和计算机断层成像显示肠道水肿，组织学分析显示结肠非特异性炎症和水肿。大多数症状在几天内自发消失。患者的父亲、姐姐和弟弟也经历了四肢、嘴唇、面部和外生殖器的反复浮肿。我们检测了所有家庭成员的血清补体水平并进行了SERPING1基因分析。检测到血清补体(C4)和c1-异烟肼水平降低，患者在SERPING1外显子7的14236位核苷酸发生单碱基转换(T到A)杂合，导致第390密码子的异亮氨酸被天冬酰胺取代，这是该家族中观察到的I型HAE型的原因(表1，图1)。值得注意的是，患者6的c1-INH蛋白水平略低，类似于HAE II型。然而，患者1的c1-inh突变导致c1-inh蛋白大量减少。因此，我们对这家人进行了I型HAE的诊断。来自日本的健康个体的100条染色体中未发现I390N突变。HAE患者有时会被误诊或忽视；因此，在日本，出现症状和诊断之间的平均间隔为13.8年。1虽然大多数HAE患者在20岁时出现窒息，但即使是年幼的儿童也可以发生窒息。2准确的HAE诊断可能会降低患者本人及其亲属因喉部受累而窒息的风险，后者也有可能发展为HAE。3早期诊断是关键，因为肿胀的第一个病例可能会危及生命。在日本，有两种药物可用于治疗HAE，人的C1-INH和缓激肽B2受体拮抗剂；然而，由于医生对HAE的认识不佳、药物有效期和成本，当HAE发作时，这些药物并不总是可用的。4由于窒息的治疗需要迅速采取行动，管理HAE患者的医生和携带缺陷基因的个人应该保持HAE药物的库存，以应对血管水肿症状的发展。遗传分析显示，患者的亲属中SERPING1突变，他们没有经历过血管水肿。如果医生诊断出一名HAEI型患者，他们还应该检查所有上升线上的一级亲属(包括无症状的个人)，如…
Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent episodes of angioedema or deep localized swelling, without urticarial rash. HAE most often affects the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts, and laryngeal involvement may result in lethal asphyxiation. In most cases, HAE occurs as a result of mutations in the SERPING1 gene, which encodes the serine protease C1 inhibitor (C1-INH); HAE type I results from C1-INH deficiency, while type II is caused by C1-INH dysfunction. 1 Here, we report a family with HAE type I carrying a novel missense mutation in SERPING1. The study protocol was approved by the Institutional Review Board of the Japanese Red Cross Wakayama Medical Center (no. 548). Patient 6 was a 31-year-old male who presented following two attacks of angioedema of the extremities, lips, face, genitals, and abdomen over a 2 year period, without respiratory symptoms. The trigger for his first episode was contracting hand-foot-mouth disease in his late twenties, while the trigger for the second episode, which occurred 1 year after the first, was unknown. Fiberoptic examination of the colon and computed tomography imaging revealed intestinal edema, and histological analysis showed nonspecific inflammation and edema of the colon. The majority of symptoms resolved spontaneously within a few days. The patient's father, older sister, and younger brother had also experienced recurrent edema of the extremities, lips, face, and external genitalia. We examined serum complement levels and performed SERPING1 gene analysis for all family members. Decreased levels of serum complement (C4) and C1-INH were detected, and patients were heterozygous for a single base pair transition (T to A) at nucleotide 14236 of exon 7 of SERPING1, leading to an amino acid substitution of isoleucine at codon 390 by asparagine, accounting for the HAE type I observed in this family (Table 1, Fig. 1). It is noteworthy that the level of C1-INH protein of patient 6 was marginally low, resembling HAE type II. However, the same mutation in C1-INH in patient 1 developed a large reduction of C1-INH protein. We, therefore, made a diagnosis of HAE type I for the family. The I390N mutation was not present in 100 chromosomes from healthy individuals originating from Japan. HAE patients are sometimes misdiagnosed or overlooked; hence, the mean interval between the onset of symptoms and diagnosis is 13.8 years in Japan. 1 Although most patients with HAE present with asphyxiation aged 20 years, asphyxiation can occur even in young children. 2 A precise HAE diagnosis may reduce the risk of suffocation due to laryngeal involvement, both for patients themselves and for their relatives, who may also potentially develop HAE. 3 Early diagnosis is key, as the first instance of swelling can be life threatening. In Japan, two drugs are available for the treatment of HAE, human C1-INH and bradykinin B2 receptor antagonists; however, these drugs are not always available when an attack occurs, due to the poor recognition of HAE by physicians, drug expiration dates, and cost. 4 As prompt action is required for the treatment of asphyxia, physicians managing HAE patients and individuals carrying the defective gene should maintain a stock of HAE drugs in anticipation of the development of angioedema symptoms.Genetic analysis revealed mutation of SERPING1 in the patient's relatives, who had experienced no episodes of angioedema. If physicians diagnose one HAE type I patient, they should also examine all first-degree relatives in the ascending line (including symptomfree individuals), as …