Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.
- MeSH
- hereditární angioedémy * diagnóza epidemiologie genetika MeSH
- inhibiční protein komplementu C1 * genetika MeSH
- lidé MeSH
- messenger RNA MeSH
- sestřih RNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
INTRODUCTION: Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH) is rare but a potentially life-threatening disease. There are no official prevalence data, nor approved therapies for this condition. OBJECTIVE: In this study, we aimed to collect and analyze clinical data on patients with AAE-C1-INH in the Czech Republic. METHODS: We have conducted a retrospective analysis of AAE-C1-INH patients from Czech referral centers for the treatment of hereditary angioedema with C1 inhibitor deficiency. The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less. RESULTS: A total of 14 patients (7 males and 7 females) met the inclusion criteria for AAE-C1-INH. The median age of the symptom onset was 59.5 years, and the median diagnosis delay was 1 year. The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%). All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate. Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%). We were not able to identify any underlying disease only in 1 patient (7%). In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms' disappearance and complement parameter normalization was observed. CONCLUSIONS: The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000. This rare condition occurs in approximately 8% of the patients with angioedema with C1 inhibitor deficiency. AAE-C1-INH is strongly associated with lymphoproliferative disorders, and treating these conditions may improve the control of angioedema symptoms.
- MeSH
- biologické markery MeSH
- dospělí MeSH
- hereditární angioedémy diagnóza epidemiologie etiologie terapie MeSH
- inhibiční protein komplementu C1 genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- management nemoci MeSH
- náchylnost k nemoci MeSH
- ochrana veřejného zdraví MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- určení symptomu MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
PURPOSE: Hereditary angioedema (HAE) is a rare autosomal dominant life-threatening disease characterized by low levels of C1 inhibitor (type I HAE) or normal levels of ineffective C1 inhibitor (type II HAE), typically occurring as a consequence of a SERPING1 mutation. In some cases, a causal mutation remains undetected after using a standard molecular genetic analysis. RESULTS: Here we show a long methodological way to the final discovery of c.1029 + 384A > G, a novel deep intronic mutation in intron 6 which is responsible for HAE type I in a large family and has not been identified by a conventional diagnostic approach. This mutation results in de novo donor splice site creation and subsequent pseudoexon inclusion, the mechanism firstly described to occur in SERPING1 in this study. We additionally discovered that the proximal part of intron 6 is a region potentially prone to pseudoexon-activating mutations, since natural alternative exons and additional cryptic sites occur therein. Indeed, we confirmed the existence of at least two different alternative exons in this region not described previously. CONCLUSIONS: In conclusion, our results suggest that detecting aberrant transcripts, which are often low abundant because of nonsense-mediated decay, requires a modified methodological approach. We suggest SERPING1 intron 6 sequencing and/or tailored mRNA analysis to be routinely used in HAE patients with no mutation identified in the coding sequence.
- MeSH
- dítě MeSH
- dospělí MeSH
- exony genetika MeSH
- hereditární angioedém, typy I a II genetika MeSH
- inhibiční protein komplementu C1 genetika MeSH
- introny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- místa sestřihu RNA genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- mutační analýza DNA metody MeSH
- rodokmen MeSH
- senioři MeSH
- splicing proteinů genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mutations in the C1 inhibitor (C1INH) encoding gene, SERPING1, are associated with hereditary angioedema (HAE) which manifests as recurrent submucosal and subcutaneous edema episodes. The major C1INH function is the complement system inhibition, preventing its spontaneous activation. The presented study is focused on SERPING1 exon 3, an alternative and extraordinarily long exon (499 bp). Endogenous expression analysis performed in the HepG2, human liver, and human peripheral blood cells revealed several exon 3 splicing variants alongside exon inclusion: a highly prevalent exon skipping variant and less frequent +38 and -15 variants with alternative 3' splice sites (ss) located 38 and 15 nucleotides downstream and upstream from the authentic 3' ss, respectively. An exon skipping variant introducing a premature stop codon, represented nearly one third of all splicing variants and surprisingly appeared not to be degraded by NMD. The alternative -15 3' ss was used to a small extent, although predicted to be extremely weak. Its use was shown to be independent of its strength and highly sensitive to any changes in the surrounding sequence. -15 3' ss seems to be co-regulated with the authentic 3' ss, whose use is dependent mainly on its strength and less on the presence of intronic regulatory motifs. Subtle SERPING1 exon 3 splicing regulation can contribute to overall C1INH plasma levels and HAE pathogenesis.
- MeSH
- alternativní sestřih genetika MeSH
- buněčné jádro genetika MeSH
- buňky Hep G2 MeSH
- exony genetika MeSH
- inhibiční protein komplementu C1 genetika MeSH
- lidé MeSH
- malá interferující RNA metabolismus MeSH
- místa sestřihu RNA genetika MeSH
- mutace genetika MeSH
- nonsense mediated mRNA decay genetika MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hereditární angioedém je vrozená porucha C1 inhibitoru systému komplementu. Je řazen mezi primární imunodeficity. Článek shrnuje patogenezi, klinické příznaky (otoky kožní a slizniční), diferenciální diagnostiku (odlišení získaného angioedému) a uvádí současné možnosti diagnostiky (imunologické a genetické). Dále je pojednáno o současných terapeutických doporučeních a postupech, o léčbě akutní a profylaktické a o možnostech léčby postižených pacientů v rámci České republiky. Zmíněny jsou i problémy, s nimiž se imunologové při léčbě potýkají.
Hereditary angioedema is a congenital defect of the C1 inhibitor system of complement. It ranks among the primary immunodeficiencies. This article summarizes the pathogenesis, clinical symptoms and signs, manifestations (edema of the skin and mucosa), differential diagnosis (differentiation from acquired angioedema) and reports on the current diagnostic (immunological and genetic) options. It also discusses the current therapeutic recommendations and procedures, including acute and prophylactic treatment as well as the therapeutic options for the treatment of patients in the Czech Republic. The article also mentions the problems faced by immunologists when providing such treatment.
- Klíčová slova
- léčba profylaktická, léčba akutní, diagnostika, C1 inhibitor,
- MeSH
- akutní nemoc terapie MeSH
- aplikace kožní MeSH
- bradykinin MeSH
- chemoprofylaxe metody využití MeSH
- dítě MeSH
- dospělí MeSH
- hereditární angioedémy * diagnóza farmakoterapie genetika MeSH
- inhibiční protein komplementu C1 * farmakologie genetika terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- prevalence MeSH
- receptor bradykininu B2 * antagonisté a inhibitory MeSH
- rekombinantní proteiny * farmakologie terapeutické užití MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
Účel prehľadu: Účelom tejto prehľadovej práce je zhrnutie klinických aspektov a liečby postihnutia horných dýchacích ciest u pacientov trpiacich hereditárnym angioedémom. Nové poznatky: V publikáciách zaoberajúcich sa molekulárnymi mechanizmami vzniku hereditárneho angioedému sa usudzuje, že sa jedná o autozomálne dominantne dedičné ochorenie charakterizované deficitom inhibítora C1 v dôsledku mutácie jeho génu (SERPING). Hereditárny angioedém sa prejavuje epizódami lokalizovaného opuchu na akomkoľvek mieste na tele, od kože, tráviaceho systému až po horné dýchacie cesty, kde môže byť opuch závažný a život ohrozujúci. Vek v čase nástupu klinických príznakov, frekvencia atakov, ako aj faktory spúšťajúce opuch horných dýchacích ciest pri hereditárnom angioedéme sú variabilné medzi rôznymi pacientmi. Akútny laryngeálny edém by mal byť riešený urgentne spolu s monitorovaním priechodnosti dýchacích ciest. Aby sa zabránilo vzniku obštrukcie dýchacích ciest, liečba by mala začať čo najskôr a mala by pozostávať zo súčasne dostupných prípravkov (koncentrát inhibítora C1) alebo z nedávno vyvinutých nových liekov. U pacientov s opakovaným opuchom horných dýchacích ciest je odporučená dlhodobá profylaktická liečba. Súhrn: Použitie starších aj nových terapeutických modalít v liečbe akútnych atakov, ako aj v profylaktickej liečbe (dlhodobej či krátkodobej) zmenilo prognózu pacientov s hereditárnym angioedémom s opuchom horných dýchacích ciest.
The purpose of the present review is to outline the clinical aspects and management of the upper airway involvement in the patients suffering from hereditary angioedema. RECENT FINDINGS: Molecular mechanisms of hereditary angioedema reviewed in the literature conclude that it is an autosomal dominant disorder, characterized by the deficiency of C1 inhibitor due to mutations of its gene (SERPING). Hereditary angioedema manifests as episodes of localized swelling in any site of the body from skin, gastrointestinal tract to the upper airway, where it is severe and life-threatening. The age of onset, frequency of attacks and the factors triggering upper airway swelling in hereditary angioedema are variable among different patients. Acute laryngeal edema should be managed in emergency with monitoring of airway patency. To avoid airway obstruction, therapy should begin early either with current treatment (C1 inhibitor concentrate) or with new drugs developed recently. In patients with recurrent upper airway swelling attacks, long-term prophylaxis is recommended. CONCLUSION: The use of old and new treatment in acute attacks as well as in prophylaxis (long and short-term) has changed the outcome of patients with hereditary angioedema who present upper airway swelling.
- MeSH
- asfyxie MeSH
- chromozomální poruchy MeSH
- diferenciální diagnóza MeSH
- dýchací soustava patologie účinky léků MeSH
- edém MeSH
- hereditární angioedémy MeSH
- incidence MeSH
- inhibiční protein komplementu C1 genetika terapeutické užití MeSH
- lidé MeSH
- lidské chromozomy, pár 11 MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH