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.

• Klíčová slova
• C1-INH-HAE, HAE, SERPING1, genotype–phenotype relationship, hereditary angioedema, splicing, time to diagnosis,
• 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 epidemiologie   MeSH
• Názvy látek
• inhibiční protein komplementu C1 * MeSH
• messenger RNA MeSH
• SERPING1 protein, human MeSH Prohlížeč

BACKGROUND: Recurrent aphthous stomatitis is one of the most prevalent oral mucosal immunological diseases. A recent case-control study in the Egyptian population suggested that single nucleotide polymorphism Gly54Asp (rs1800450) of the mannose-binding lectin 2 gene might affect the mannose-binding lectin serum level and recurrent aphthous stomatitis development. The aim of this study was to determine the distribution of six functional mannose-binding lectin 2 gene polymorphisms and analyse their role in recurrent aphthous stomatitis susceptibility in the Czech population. METHODS: The study included 227 subjects; 137 healthy people and 90 patients with recurrent aphthous stomatitis. Six mannose-binding lectin 2 gene polymorphisms (rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, rs1800451) were analysed by the SNaPshot assay method, mannose-binding lectin serum levels were determined by enzyme-linked immunosorbent assay (ELISA) method in a subgroup of subjects (N = 87). RESULTS: No significant differences in mean of mannose-binding lectin serum levels between healthy controls and patients with recurrent aphthous stomatitis were observed (383 ng/ml ± 249 standard deviation (SD) vs. 316 ng/ml ± 177 SD in remission phase vs. 343 ng/ml ± 254 SD in active phase; p > 0.05), also the allele and genotype frequencies of the studied mannose-binding lectin 2 polymorphisms did not differ significantly between the two groups (p > 0.05, odds ratio (OR): 0.75-1.23). Moreover, the distribution of mannose-binding lectin 2 haplotypes and haplogenotypes was similar in the healthy subjects and patients with recurrent aphthous stomatitis (p > 0.05, OR: 0.75-1.23). CONCLUSIONS: This study did not confirm the previously reported association of the mannose-binding lectin 2 Gly54Asp gene variant and low mannose-binding lectin serum level as the risk factors for susceptibility to recurrent aphthous stomatitis. In addition, no significant relationships between mannose-binding lectin 2 functional haplotypes or haplogenotypes and recurrent aphthous stomatitis were observed.

• Klíčová slova
• MBL, haplogenotype, haplotype, polymorphism, recurrent aphthous stomatitis,
• MeSH
• aftózní stomatitida * genetika   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lektin vázající mannosu MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• lektin vázající mannosu MeSH

• MeSH
• bradykinin analogy a deriváty   terapeutické užití   MeSH
• hereditární angioedémy * diagnóza   farmakoterapie   MeSH
• inhibiční protein komplementu C1 genetika   terapeutické užití   MeSH
• lidé MeSH
• registrace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• Názvy látek
• bradykinin MeSH
• icatibant MeSH Prohlížeč
• inhibiční protein komplementu C1 MeSH

BACKGROUND: Recurrent aphthous stomatitis (RAS) is multifactorial disease with unclear etiopathogenesis. The aim of this study was to determine distribution of the angiotensin I converting enzyme (ACE) gene polymorphisms and their influence on RAS susceptibility in Czech population. METHODS: The study included 230 subjects (143 healthy controls and 87 patients with RAS) with anamnestic, clinical and laboratory data. Five ACE gene polymorphisms (rs4291/rs4305/rs4311/rs4331/rs1799752 = ACE I/D) were determined by TaqMan technique. RESULTS: The allele and genotype distributions of the studied ACE I/D polymorphisms were not significantly different between subjects with/without RAS (Pcorr > 0.05). However, carriers of II genotype were less frequent in the RAS group (OR = 0.48, 95% CI = 0.21-1.12, P = 0.059). Stratified analysis by sex demonstrated lower frequency of II genotype in women (OR = 0.33, 95% CI = 0.09-1.17, P < 0.035, Pcorr > 0.05, respectively) than in men with RAS (P > 0.05). Moreover, the frequency of AGTGD haplotype was significantly increased in RAS patients (OR = 13.74, 95% CI = 1.70-110.79, P = 0.0012, Pcorr < 0.05). In subanalysis, TGD haplotype was significantly more frequent in RAS patients (P < 0.00001) and CGI haplotype was less frequent in RAS patients (P < 0.01), especially in women (P = 0.016, Pcorr > 0.05). CONCLUSIONS: Our study indicates that while the AGTGD and TGD haplotypes are associated with increased risk of RAS development, CGI haplotype might be one of protective factors against RAS susceptibility in Czech population.

• Klíčová slova
• Angiotensin I converting enzyme, Haplotype, Polymorphism, Recurrent aphthous stomatitis, Sex difference,
• MeSH
• aftózní stomatitida * epidemiologie   genetika   MeSH
• angiotensin konvertující enzym * genetika   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• polymorfismus genetický MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ACE protein, human MeSH Prohlížeč
• angiotensin konvertující enzym * 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.

• Klíčová slova
• Acquired angioedema, Bradykinin, C1 inhibitor, Lymphoma,
• 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 epidemiologie   MeSH
• Názvy látek
• biologické markery MeSH
• inhibiční protein komplementu C1 MeSH
• SERPING1 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• Hereditary angioedema, SERPING1, donor splice site, pre-mRNA splicing, pseudoexon activation,
• 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
• Názvy látek
• inhibiční protein komplementu C1 MeSH
• místa sestřihu RNA MeSH

BACKGROUND: The development of recurrent aphthous stomatitis (RAS), inflammatory disease of oral mucosa, is influenced by both environmental and genetic factors. The aim of this study was to investigate polymorphisms located in seven genes coding different types of matrix metalloproteinases (MMPs)-collagenases (MMP1, MMP8, and MMP13), gelatinases (MMP2 and MMP9), stromelysin (MMP3), and membrane-type metalloproteinase (MMP16) in patients with RAS and healthy controls. METHODS: Totally, 223 subjects were included in this case-control study and their detailed anamnestic, clinical, and laboratory parameters were recorded. Seventy-seven patients with RAS and 146 controls were genotyped for seventeen polymorphisms in the MMPs genes using the real-time polymerase chain reaction (PCR) or PCR with restriction analysis. RESULTS: Allele, genotype, and haplotype frequencies of the studied polymorphisms between RAS patients and controls were similar, except for allele distributions of MMP1 rs1144393, MMP9 rs3918242, and MMP16 rs10429371, which were different between patients with RAS and healthy controls (P = .023, P = .049 and P = .025, all Pcorr > 0.05, respectively). Moreover, the comparison of genotype frequencies (TT vs CC + CT) of the MMP16 rs10429371 variant showed a marginally significant difference between RAS patients and controls (P = .05, Pcorr > 0.05, OR = 1.68, 95% CI = 0.95-2.98). CONCLUSIONS: No significant relationship between investigated polymorphisms in seven MMPs genes and RAS development in the Czech population was observed in this study.

• Klíčová slova
• case-control study, matrix metalloproteinase, polymorphism, recurrent aphthous stomatitis,
• MeSH
• aftózní stomatitida enzymologie   genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• haplotypy MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• matrixové metaloproteinasy genetika   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• matrixové metaloproteinasy MeSH

OBJECTIVE: The aim of this study was to investigate five polymorphisms in the SLC6A4 gene in patients with recurrent aphthous stomatitis (RAS) and healthy controls. DESIGN: Totally, 239 subjects were enrolled in this case-control study: 86 patients with RAS and 153 healthy individuals were genotyped for serotonin transporter length polymorphic region (5-HTTLPR) polymorphism, variable number tandem repeat (STin2) and single nucleotide polymorphisms (rs25531, rs3813034, rs1042173) in the SLC6A4 gene by polymerase chain reaction with/without restriction analysis. RESULTS: No significant differences in the allele or genotype frequencies in all studied polymorphisms between RAS patients and healthy controls (P > 0.05) were detected. However, the haplotype analysis detected a higher frequency of LA12 (HTTLPR, rs25531, STin2) haplotype in RAS patients in comparison with healthy controls (P < 0.05, OR = 1.63, 95 % CI = 1.07-2.49). CONCLUSIONS: Our study indicates a possible relationship between SLC6A4 and susceptibility to RAS in the Czech population.

• Klíčová slova
• Polymorphism, Recurrent aphthous stomatitis, SLC6A4, Serotonin transporter gene,
• MeSH
• aftózní stomatitida * genetika   MeSH
• frekvence genu MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin * genetika   MeSH
• recidiva MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin * MeSH
• SLC6A4 protein, human MeSH Prohlížeč

Genetic factors, especially those related to immune system functioning, have been intensively studied to determine their role in the development of recurrent aphthous stomatitis (RAS). The aim of the present study was to analyze gene variability in interleukin (IL)2, IL4 (and its receptor α, IL4Rα), IL10, and IL13, which were selected based on literature review and/or their functional relevance, in Czech patients with RAS and in healthy controls. In total, 252 subjects (178 controls and 74 patients with RAS) were enrolled in this case-control study, and their detailed anamnestic, clinical, and laboratory data were obtained. Nine polymorphisms in the genes encoding interleukins were determined using PCR techniques. There were no significant differences in allele or genotype frequencies of the IL2, IL4, IL4Rα, IL10, and IL13 polymorphisms rs2069762/rs2069763, rs2243250/rs79071878, rs1801275, rs1800896, and rs1800925, respectively, between controls and patients with RAS. The minority alleles rs1800871 and rs1800872, which encode variants of IL10, were associated with a statistically significantly higher risk of RAS, as confirmed by the results of genotype and haplotype analyses. We suggest that variability in the IL10 gene may play an important role in the development of RAS in the Czech population.

• Klíčová slova
• association studies, candidate gene, genetic, immunity, oral ulcer, polymorphisms,
• MeSH
• aftózní stomatitida epidemiologie   imunologie   MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genetická variace * MeSH
• genotyp MeSH
• haplotypy MeSH
• interleukin-10 genetika   metabolismus   MeSH
• interleukin-13 genetika   metabolismus   MeSH
• interleukin-2 genetika   MeSH
• interleukin-4 genetika   metabolismus   MeSH
• interleukiny genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární epidemiologie * MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus genetický MeSH
• receptor interleukinu-4 - alfa-podjednotka genetika   metabolismus   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• IL10 protein, human MeSH Prohlížeč
• IL2 protein, human MeSH Prohlížeč
• IL4 protein, human MeSH Prohlížeč
• IL4R protein, human MeSH Prohlížeč
• interleukin-10 MeSH
• interleukin-13 MeSH
• interleukin-2 MeSH
• interleukin-4 MeSH
• interleukiny MeSH
• receptor interleukinu-4 - alfa-podjednotka MeSH

PURPOSE: Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches. METHODS: We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients. RESULTS: During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690 g. No congenital abnormalities were detected in the neonates. No abortions occurred. CONCLUSIONS: Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

• Klíčová slova
• Hereditary angioedema, icatibant, pregnancy, recombinant C1 inhibitor, therapy,
• MeSH
• antiflogistika nesteroidní terapeutické užití   MeSH
• bradykinin analogy a deriváty   terapeutické užití   MeSH
• dospělí MeSH
• hereditární angioedémy diagnóza   farmakoterapie   genetika   MeSH
• inhibiční protein komplementu C1 aplikace a dávkování   terapeutické užití   MeSH
• komplikace těhotenství * MeSH
• lidé MeSH
• mladý dospělý MeSH
• progrese nemoci MeSH
• rekombinantní proteiny aplikace a dávkování   terapeutické užití   MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• trimestry těhotenství MeSH
• vedení porodu MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• bradykinin MeSH
• icatibant MeSH Prohlížeč
• inhibiční protein komplementu C1 MeSH
• rekombinantní proteiny MeSH