遗传性血管性水肿

遗传性血管性水肿(HAE)是一种少见的常染色体显性遗传病,由C1酯酶抑制剂(C1INH)基因突变引起,以发作性皮下和黏膜下组织水肿为特征,水肿累及皮肤、呼吸道、胃肠道等多个器官组织。因其发病率低,临床表现多样常难以诊断。现就该病的发病机制、临床特点和治疗作一综述。     

美国食品药品管理局批准重组C1酯酶抑制剂(ruconest)治疗遗传性血管性水肿

<正>美国食品药品管理局(FDA)已批准了第一个血浆重组C1酯酶抑制剂(ruconest)用于治疗青少年及成人的遗传性血管性水肿急性发作(hereditary angioedema,HAE)。HAE是一种罕见的并有潜在生命危险的基因异常性疾病,导致患者C1酯酶抑制剂缺陷。这种具有复发性、自限性的水肿主要发生在四肢、肠道、面部及咽喉。若呼吸道肿胀不立即治疗可致命。50 IU/kg的ruconest可恢复血浆中具有功能的C1酯酶抑制剂的水平,从而可治疗HAE的急性发作,     

遗传性血管性水肿的研究进展

遗传性血管性水肿是一种由于C1酯酶抑制剂的合成障碍或功能缺陷所致的常染色体显性遗传病。该病尚无满意治疗,但最近研究发现其发病的主要介质是缓激肽,故激肽释放酶抑制剂和缓激肽2型受体拮抗剂成为新药研发的热点,为治疗提供了更多的选择。对遗传性血管性水肿的病因及发病机制、临床表现及分型、治疗进行概述。     

获得性CI酯酶抑制剂缺乏与血管性水肿

血管性水肿是多种原因引起的血管渗透性增加,血管内浆液和蛋白渗出至皮下及粘膜而发生的水肿,其病因有过敏反应、物理及C_1酯酶抑制剂(C_1INH)缺乏(遗传性或获得性)等等因素.临床上遗传性血管性水肿(HAE,即遗传性C_1INH缺乏)除肢端、面部反复发生实质性非瘙痒性水肿外,还累及呼吸道及腹部内脏,后者表现为严重的痉挛性腹痛、恶心、     

遗传性血管性水肿C1INH基因1440V变异及其对结构的影响

目的 通过基因测序了解遗传性血管性水肿(HAE)患者C1酯酶抑制剂(C1INH)基因第八外显子的变异情况.方法 从HAE患者外周血白细胞中提取基因组DNA,PCR扩增第八外显子片段后插入pUC19质粒载体冉转化入感受态大肠杆菌TG1菌株,培养扩增质粒DNA,提取纯化后进行基因测序.将患者血清进行SDS-PAGE及Westem印迹,以了解该变异对CIINH结构的可能影响.结果 在1例I型HAE患者的第八外显子中发现一个变异位点,16776A＞G,致440位的异亮氨酸突变成缬氨酸(1440V),SDS-PAGE及Westem印迹显示该患者血清中C1INH全部表现为96 000片段而非正常的105 000片段.结论 1440v是一个新的C1INH基因变异,位于C1INH反应中心环的P4位,变异可能导致C1INH分子构象发生改变.     

遗传性对称性色素异常症分子遗传学研究进展

遗传性对称性色素异常症是一种较为少见的常染色体显性遗传性皮肤病。近年来该病的分子遗传学研究取得了很大的进展,致病基因已确定为1q11-q21上的ADAR基因,其编码的产物为RNA特异性腺嘌呤核苷酸脱氨酶。综述该病的致病基因定位、ADAR基因的结构、基因编码的产物、功能以及基因突变与疾病表型之间的关系。     

遗传性对称性色素异常症分子遗传学研究进展

遗传性对称性色素异常症是一种较为少见的常染色体显性遗传性皮肤病。近年来该病的分子遗传学研究取得了很大的进展，致病基因已确定为1q11-q21上的ADAR基因，其编码的产物为RNA特异性腺嘌呤核苷酸脱氨酶。综述该病的致病基因定位、ADAR基因的结构、基因编码的产物、功能以及基因突变与疾病表型之间的关系。     

遗传性血管性水肿1家系C1抑制物基因突变分析

目的对一个中国遗传性血管性水肿家系进行C1抑制物(C1INH)基因突变检测分析。方法采用聚合酶链反应(PCR)和直接测序法检测C1INH基因8个外显子及每个外显子与内含子的相邻序列,将检测结果与GenBank公布的C1INH基因正常序列进行比较。为除外基因多态性可能,在50名正常人群对照中对该突变进行分析。血清补体C_4和C1INH浓度采用速率散射比浊法测定,血清C1INH功能水平通过酶联免疫吸附试验(ELISA)测定。结果 4例患者的第3外显子均检测到1个无义突变(c.400GT),该突变导致编码第134位的谷氨酸变为终止密码子(p.E134X)。家系中4例正常对照和50例健康人群对照未检测到该突变。4例患者的血清C_4浓度、C1INH浓度及功能水平均低于正常值下限。该家系中2例正常对照和2例健康人群对照血清C_4浓度、C1INH浓度及功能水平均在正常范围内。结论在该家系中发现C1INH基因突变c.400GT,该突变为此家系发病的分子基础。     

遗传性单纯性少毛症1例及SNRPE基因突变研究

目的:报告国内首例由SNRPE基因突变导致的常染色体显性遗传性单纯性少毛症(少毛症11型)1例,并对其家系进行基因突变研究。方法:抽取患儿及其父母外周血,提取血液基因组DNA,同时取100例健康汉族人基因组DNA样品作对照,采用PCR方法扩增APCDD1、RPL21、SNRPE、HR基因所有外显子及其侧翼序列,并对产物进行测序分析。结果:患儿SNRPE基因存在剪切位点杂合突变,c.144+4AC。患儿父母及100例健康对照均未发现该杂合突变。结论:SNRPE基因的杂合突变c.144+4AC可能为导致该遗传性单纯性少毛症家系的原因。     

遗传性对称性色素异常症三家系ADAR1基因突变检测

【摘要】 目的 探讨3个遗传性对称性色素异常症家系中ADAR1基因的突变情况。方法 收集血样,用PCR结合DNA直接测序的方法,检测3个家系中的患者、患者亲属及与家系无关的50例健康个体的ADAR1基因突变情况。 结果 所研究的3个家系中均存在ADAR1基因的异常。包括A及C家系中2个错义突变（c.1760A > G导致p.Y587C,c.3620G > T导致p.G1207V）,B家系中1个移码突变（c.2433-2434delAG）。3个家系中未患病个体和健康对照均未发现相应突变。 结论 3个ADAR1基因突变中,2个错义突变均为新突变,可能是导致遗传性对称性色素异常症发病的分子机制之一。     

Tissue factor expression on the surface of monocytes from a patient with hereditary angioedema

Hereditary angioedema (HAE) presents as severe angioedema, which is mostly due to the C1 inhibitor (C1‐INH) gene mutations. Environmental factors, minor trauma and oral contraceptives have been reported to induce angioedema attack, but the trigger may often be uncertain. Activated factor XII controlled by C1‐INH facilitates bradykinin generation and also regulates coagulation cascade, but the relationship between edema formation and coagulation is still unclear. We have described a 35‐year‐old female patient with HAE, presenting with frequent angioedema attacks in the absence of an apparent triggering factor. She showed higher levels of FDP and D‐dimer during angioedema than those in remission. In addition, tissue factor (TF), an initiator of the extrinsic coagulation cascade, was expressed on the surface of monocytes. It was significantly higher than that of monocytes from healthy controls and tends to further increase during attacks. The expression of TF on monocytes may play a role in the induction of angioedema attacks in HAE by activating the coagulation pathway in association with reduced functions of C1‐INH.     

A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I

C1 inhibitor (C1INH) plays an important role in the classical pathway of the complement system. Mutations in C1INH gene cause quantitative or qualitative deficiencies in C1INH, which can lead to hereditary angioedema (HAE) type I or II. Here, we identified a novel frame‐shift mutation c.1391‐1445del55 (p.v464fsx556) in exon 8 in a large Chinese family with HAE type I. This 55 base pairs deletion abolishes the original stop codon and introduces a new stop codon 220 bp downstream of the original one, and leads to mutated C1INH protein prolonged from 500 to 556 amino acids. The levels of C4 and C1INH as well as C1INH activity in serum were significantly reduced in affected individuals. This is the first report of a novel mutation abolishing the physiological stop codon of C1INH gene in a large Chinese family with HAE type I.     

Treatment of hereditary angio-oedema by low dose attenuated androgens: disassociation of clinical response from levels of C1 esterase inhibitor and C4

Nine patients with hereditary angio-oedema (H. A. E.) with a deficiency of C1 esterase inhibitor (CI INH), have been treated with low dose attenuated androgenic drugs, with complete control of their disease. The CI esterase inhibitor and C4 levels became normal in only one patient. It is concluded that H. A. E. can be controlled in the absence of correction of the reduced levels of C1 INH and C4. The mode of action of these drugs appears to be more complex than is generally realized.     

Use of recombinant C1 inhibitor in patients with resistant or frequent attacks of hereditary or acquired angioedema

Background

Conestat alfa (Ruconest, rhC1INH) is the first recombinant human C1 inhibitor protein (C1INH) for the treatment of acute attacks of hereditary angioedema (HAE).

Objective

To assess clinical experience of the first 11 adult patients who received rhC1INH in clinical practice in the UK.

Methods

Eleven patients (nine HAE type 1, one HAE type 2 and one acquired angioedema with C1 inhibitor deficiency) received between one and six, mostly self-administered, doses of rhC1INH for acute HAE attacks. They were asked to record their time to first response and complete resolution following the treatment. This cohort included our most severely affected and difficult to treat patients.

Results

In most cases, time to first improvement following rhC1INH and complete resolution was recorded as comparable to their typical response to pdC1INH, although 4/11 patients reported that the time to first improvement was much quicker than their average pdC1INH response. Five of the 11 patients continued with rhC1INH as their preferred rescue treatment. Of those who chose not to continue the treatment, four reported a recurrence or early return of symptoms with rhC1INH.

Conclusion

In our experience, rhC1INH is a beneficial treatment for patients with preference for a C1INH that is not plasma derived and it is suitable for home treatment. In some cases it demonstrates cost saving, especially for heavier patients who require higher doses. In some patients rhC1INH may result in faster resolution of symptoms. It may be associated with an early return of symptoms in patients with exceptionally frequent attacks.

     

The genetic basis of seborrhoeic dermatitis: a review

Seborrhoeic Dermatitis (SD) is a common inflammatory skin disease that presents as itchy, flaking skin in the seborrhoeic areas. Various environmental and intrinsic factors have been identified as predisposing factors for SD, but its aetiology remains poorly understood. Although it was recognized that genetic factors play a role in SD aetiology, there have not been studies that systematically review the literature specifically for causal mutations or protein deficiencies in SD. In this review, we searched various databases for gene mutations and protein deficiencies that cause SD or SD‐like phenotype in humans and experimental animals, and summarize 11 gene mutations or protein deficiencies that were described in the literature. Most of the encoded proteins play a role either in the immune response (ACT1, C5, IKBKG/NEMO, STK4, 2C TCR) or epidermal differentiation (ZNF750, MPZL3). Understanding the genetic basis of SD can impart knowledge of the pathobiology of the disease and help identify novel therapeutic targets.     

Four novel ATP2C1 mutations in Chinese patients with Hailey–Hailey disease

Hailey–Hailey disease (HHD) is a kind of autosomal dominant dermatosis. The ATP2C1 gene has been identified as the pathogenic gene of HHD since 2000. In this study, direct DNA sequencing was used to identify ATP2C1 gene mutations in four Chinese families and two sporadic cases with HHD. The entire coding and flanking intronic sequences of ATP2C1 were screened for mutations and five heterozygous mutations of the ATP2C1 gene were detected in the four pedigrees and two sporadic cases with HHD. Four of them were novel, including three frame‐shift mutations (c.1330delC, c.888_889insT, c.478_479insA) and one nonsense mutation (c.1720C>T). These data added new variants to the database of ATP2C1 mutations associated with HHD.     

Four novel mutations in ATP2C1 found in Chinese patients with Hailey-Hailey disease

BACKGROUND: Familial benign chronic pemphigus or Hailey-Hailey disease (HHD; OMIM 169600) is an autosomal dominant blistering disease. Pathogenic mutations in ATP2C1 encoding a novel Ca2+ pump have recently been identified. OBJECTIVES: To identify mutations in ATP2C1 in Chinese patients with HHD. METHODS: Eleven unrelated Chinese patients with HHD were subjected to mutation detection in ATP2C1. Eight of them had a family history of HHD. The 27 coding exons and their flanking sequences were amplified and sequenced. RESULTS: Five of the 11 patients were identified to have heterozygous mutations including three nonsense mutations and two splicing mutations in ATP2C1. CONCLUSIONS: Four novel mutations, nonsense mutations S887X and W795X and splicing mutations 118-1 g-->a and 1890+1del(gtgag)ins53, were found in this series of Chinese patients with HHD.