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Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare inborn error of immunity that presents with episodic swelling. Management is multifaceted and includes on-demand treatment of swelling episodes, short-term prophylaxis to prevent swelling episodes from procedures, and long-term prophylaxis (LTP) to prevent angioedema on an ongoing basis. All approved on-demand therapies are parenteral, necessitating patient training for home administration, particularly intravenous C1 inhibitor. These complexities can result in care gaps for rural HAE patients. We conducted a cross-sectional study at our Angioedema Center of Reference and Excellence to assess the care provided to urban and rural patients. The proportion of patients receiving LTP, proportion of patients diagnosed as children, and disease control measured using the Angioedema Control Test (AECT) were collected. Logistic and Poisson regression models adjusted for age and sex were used to compare the two groups. The proportion using LTP was similar at 62% and 61% in urban and rural patients, respectively (odds ratio [OR] 1.01 (CI 95% 0.34-2.99)). Among urban patients, 52% were diagnosed as children compared to 60% among rural residents (1.43 (0.37-5.56)). The mean (IQR) AECT score was 14.0 (8.5-15.5) in urban patients and 13.0 (10.0-14.0) in rural patients (Poisson β -0.001 (-0.23-0.23). These data indicate that rural patients received similar high-quality care. We attribute these findings to the centralized care model employed in which HAE patients in the region are seen at a single comprehensive care clinic. [ABSTRACT FROM AUTHOR]

Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare inborn error of immunity that presents with episodic swelling. Management is multifaceted and includes on-demand treatment of swelling episodes, short-term prophylaxis to prevent swelling episodes from procedures, and long-term prophylaxis (LTP) to prevent angioedema on an ongoing basis. All approved on-demand therapies are parenteral, necessitating patient training for home administration, particularly intravenous C1 inhibitor. These complexities can result in care gaps for rural HAE patients. We conducted a cross-sectional study at our Angioedema Center of Reference and Excellence to assess the care provided to urban and rural patients. The proportion of patients receiving LTP, proportion of patients diagnosed as children, and disease control measured using the Angioedema Control Test (AECT) were collected. Logistic and Poisson regression models adjusted for age and sex were used to compare the two groups. The proportion using LTP was similar at 62% and 61% in urban and rural patients, respectively (odds ratio [OR] 1.01 (CI 95% 0.34-2.99)). Among urban patients, 52% were diagnosed as children compared to 60% among rural residents (1.43 (0.37-5.56)). The mean (IQR) AECT score was 14.0 (8.5-15.5) in urban patients and 13.0 (10.0-14.0) in rural patients (Poisson β -0.001 (-0.23-0.23). These data indicate that rural patients received similar high-quality care. We attribute these findings to the centralized care model employed in which HAE patients in the region are seen at a single comprehensive care clinic.

Hereditary angioedema (HAE) is a rare autosomal-dominant disease that is caused by a deficiency (type I) or dysfunction (type II) of the C1 inhibitor (C1-INH) due to a mutation in the SERPING1 gene, which codes for C1-INH. HAE with quantitatively and qualitatively normal C1-INH (type III) is often caused by a mutation in the F12 gene and no mutations in the SERPING1 gene and is a group of very rare diseases. The C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases vascular permeability and allows the flow of fluids into the extracellular space, resulting in angioedema. HAE clinically manifests with intermittent attacks of swelling of the subcutaneous tissue or submucosal layers of the respiratory and gastrointestinal tract. Young children are typically asymptomatic, and those affected by HAE usually present with symptoms in their early 20s. This article describes the case of very early onset of hereditary angioedema caused by C1-INH deficiency in a 2-year-old boy who experienced recurrent episodes of hand and abdominal angioedema not associated with urticaria or pruritus. His father suffered from severe HAE due to a de novo mutation of the SERPING1 gene. The same mutation of the SERPING1 gene was detected in his son at the age of 9-months prior to the occurrence of angioedema symptoms, during genetic family counseling. This paper advances the understanding of HAE and highlights the importance of genetic counseling of families with HAE to avoid late or inaccurate diagnosis and to initiate treatment on time.

Objective: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. Methods and analysis: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. Results: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10−5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (−0.43, −0.62 to −0.23, p = 2.08 × 10−5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. Conclusions: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance. [ABSTRACT FROM AUTHOR]

Hereditary angioedema is a rare, potentially life-threatening disease. There is a lack of data describing the clinical course of hereditary angioedema (HAE) in children. We aimed to evaluate the clinical characteristics of pediatric patients with hereditary angioedema: The age of disease onset, age at diagnosis, the frequency of angioedema attacks, the total number of attacks before diagnosis, the regions where angioedema attacks were observed, accompanying abdominal pain, and serum levels of C4 and C1 esterase inhibitor were obtained and recorded. In addition, the results of SERPING1 (C1INH) gene sequence analysis of the patients in this group were also collected from medical records and recorded. While none of the patients reported a skin rash as a symptom of attack, there was formication observed in the region of angioedema in 46.9% (n = 15) of the patients and pruritus in 6.2% (n = 2) of the patients. At disease onset, the complaints of the patients regarding location of edema were on the hands of 32.3% (n = 10), on the feet of 9.7% (n = 3), on the faces of 25.7% (n = 8), and abdominal attacks in 32.3% of the patients (n = 10). Four different variants, one of which was novel, were detected in the SERPING1 gene in eight different families. The results of this study suggest that hereditary angioedema is diagnosed only when the patient requests examination following recurrent angioedema. Severe laryngeal edema attacks in patients without a diagnosis of HAE are fatal at a higher rate than attacks in patients with a diagnosis. Thus, awareness of the symptoms of HAE is necessary, and correct diagnosis is essential to proper treatment. [ABSTRACT FROM AUTHOR]

Variants that affect splice sites comprise 14.3% of all pathogenic variants in the SERPING1 gene; more than half of them are located outside the canonical sites. To make a clinical decision concerning patients with such variants, it is essential to know the exact way in which the effect of the variant would be realized. The optimal approach to determine the consequences is considered to be mRNA analysis. In the current study, we present the results of functional analysis of two previously non-described variants in the SERPING1 gene (NM_000062.3) affecting intron 4: c.686-1G>A and c.685+4dup, which were detected in members of two Russian families with autosomal dominant inheritance of angioedema type 1. Analysis of the patients' mRNA (extracted from whole blood) showed that the SERPING1(NM_000062.3):c.685+4dup variant leads to the loss of the donor splice site and the activation of the cryptic site in exon 4: r.710_745del (p.Gly217_Pro228del), while the SERPING1(NM_000062.3):c.686-1G>A variant leads to the skipping of exon 5: r.746_949del (p.Asp229_Ser296del). [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein–kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant's effects on the structure–function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) with C1‐inhibitor deficiency (C1‐INH‐HAE) is a rare disease caused by low level (type I) or dysfunction (type II) of the C1‐inhibitor protein with subsequent reduction of certain complement protein levels. Methods: To develop and test the reliability of a two‐tier method based on C1‐INH and C4 quantitation followed by genetic analysis from dried blood spot (DBS) for establishing the diagnosis of C1‐INH‐HAE. C1‐INH and C4 proteins have been quantified in human plasma using a classical immuno‐assay and in DBS using a newly developed proteolytic liquid chromatography–mass spectrometry method. Genetic analysis was carried out as reported previously (PMID: 35386643) and by a targeted next‐generation sequencing panel, multiplex ligation‐dependent probe amplification and in some cases whole genome sequencing. Results: DBS quantification of C1‐INH and C4 showed the same pattern as plasma, offering the possibility of screening patients with AE symptoms either locally or remotely. Genetic analysis from DBS verified each of the previously identified SERPING1 mutations of the tested C1‐INH‐HAE patients and revealed the presence of other rare variations in genes that may be involved in the pathogenesis of AE episodes. Conclusions: C1‐INH/C4 quantification in DBS can be used for screening of hereditary AE and DNA extracted from dried blood spots is suitable for identifying various types of mutations of the SERPING1 gene. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary angioedema (HAE) with C1‐inhibitor deficiency (C1‐INH‐HAE) is a rare disease caused by low level (type I) or dysfunction (type II) of the C1‐inhibitor protein with subsequent reduction of certain complement protein levels. Methods To develop and test the reliability of a two‐tier method based on C1‐INH and C4 quantitation followed by genetic analysis from dried blood spot (DBS) for establishing the diagnosis of C1‐INH‐HAE. C1‐INH and C4 proteins have been quantified in human plasma using a classical immuno‐assay and in DBS using a newly developed proteolytic liquid chromatography–mass spectrometry method. Genetic analysis was carried out as reported previously (PMID: 35386643) and by a targeted next‐generation sequencing panel, multiplex ligation‐dependent probe amplification and in some cases whole genome sequencing. Results DBS quantification of C1‐INH and C4 showed the same pattern as plasma, offering the possibility of screening patients with AE symptoms either locally or remotely. Genetic analysis from DBS verified each of the previously identified SERPING1 mutations of the tested C1‐INH‐HAE patients and revealed the presence of other rare variations in genes that may be involved in the pathogenesis of AE episodes. Conclusions C1‐INH/C4 quantification in DBS can be used for screening of hereditary AE and DNA extracted from dried blood spots is suitable for identifying various types of mutations of the SERPING1 gene.

Our understanding of the gastrointestinal system in the pathophysiology of Parkinson's disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and relaxation of smooth muscle and inflammation responses, by applying the serping1 siRNA were investigated in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD mice in an α-syn change aspect. In the result, serping1 expression was knocked down by the treatment of serping1 siRNA, and decreased serping1 induced the decrease α-syn in the colon. Furthermore, the changes in α-syn aggregation were also examined in the brain, and alleviated α-syn aggregation was also observed in an serping1 siRNA treatment group. The results indicated that serping1 siRNA could ease synucleinopathy related to the gastrointestinal system in PD. This study also raises the possibility that serping1 siRNA could alleviate α-syn aggregation in striatum and substantia nigra regions of the brain. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1). The clinical presentation of HAE varies between patients, but it usually presents with nonpitting angioedema and occasionally abdominal pain. Young children are typically asymptomatic. Those affected by HAE usually present with symptoms in their early 20s. Symptoms can arise as a result of stress, infection, or trauma. Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin. C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected. Acute treatment of HAE can include IV infusions of C1-INH, receptor antagonists, and kallikrein inhibitors. Short- and long-term prophylaxis can also be administered to patients with HAE. First-line therapies for long-term prophylaxis also include IV infusion of C1-INH. This review aims to thoroughly understand HAE, its clinical presentation, and how to treat it. [ABSTRACT FROM AUTHOR]

Variants that affect splice sites comprise 14.3% of all pathogenic variants in the SERPING1 gene; more than half of them are located outside the canonical sites. To make a clinical decision concerning patients with such variants, it is essential to know the exact way in which the effect of the variant would be realized. The optimal approach to determine the consequences is considered to be mRNA analysis. In the current study, we present the results of functional analysis of two previously non-described variants in the SERPING1 gene (NM_000062.3) affecting intron 4: c.686-1G>A and c.685+4dup, which were detected in members of two Russian families with autosomal dominant inheritance of angioedema type 1. Analysis of the patients’ mRNA (extracted from whole blood) showed that the SERPING1(NM_000062.3):c.685+4dup variant leads to the loss of the donor splice site and the activation of the cryptic site in exon 4: r.710_745del (p.Gly217_Pro228del), while the SERPING1(NM_000062.3):c.686-1G>A variant leads to the skipping of exon 5: r.746_949del (p.Asp229_Ser296del).

Abstract Background Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe swellings of the skin and submucosa. More than 900 variants of the SERPING1 gene associated with HAE have been identified. However, only approximately 50 variants have been identified in the Chinese population. This study aimed to update the mutational spectrum in Chinese HAE patients and provide evidence for the accurate diagnosis of HAE. Methods A total of 97 unrelated HAE patients were enrolled in the study. Sanger sequencing and multiple ligation-dependent probe amplification analysis were used to identify the variants in the SERPING1 gene. The variants were reviewed in a number of databases, including the Human Gene Mutation Database (HGMD) ( http://www.hgmd.cf.ac.uk/ ) and the Leiden Open Variation Database (LOVD, https://databases.lovd.nl/shared/variants/SERPING1 ). The American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria was used to determine the pathogenicity of the variants. Results Of the 97 patients, 76 different variants were identified in 90 of them and no disease-causing variants were identified in the remaining 7 patients. Among the 76 variants, 35 variants were novel and submitted to ClinVar. Missense and in-frame variants were the most common variants (36.8%), followed by frameshift (28.9%), nonsense (14.5%), splice site (13.2%) variants, and gross deletions/duplications (6.6%). Conclusions Our findings broaden the mutational spectrum of SERPING1 and provide evidence for accurate diagnosis and predictive genetic counseling.

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder affecting roughly 1:50,000 individuals. It is commonly characterized by swelling of the larynx, gastrointestinal tract, extremities, and skin. There is growing genetic heterogeneity associated with this disease but more than 95% of mutations are found in SERPING1, the gene which encodes complement 1 inhibitor (C1-INH). HAE cohorts from several populations have been published but no large scale study has been reported from the Arab world to date. Here we document the clinical and genetic findings of HAE patients from a single Saudi institution, which is a major referral center at the national level. A total of 51 patients across 17 unrelated families were recruited including two large multi-generational families, of which one contained an in-frame exonic deletion that was resolved through MLPA. Two cases were negative for all the genes we tested (including F12, PLG, ANGPT1, MYOF, KNG1, and HS3ST6). The predominant HAE subtype in our cohort was type I, at 76%. We were able to uncover a mutation in 49 patients (96%). No type III (normal C1-INH) patients were encountered in the clinic, suggesting that this subtype does not play a major role in HAE pathogenesis in Saudi Arabia. Additionally, the existence of four patients with consistently normal complement 4 (C4) levels alongside abnormal C1-INH profiles highlights the utility of dual screening for both proteins in suspected patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence-free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib-resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP-2 and MMP-9 activity and enhanced the expression of p-ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p-ERK-MMP-2-MMP-9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC., (© 2024 The Author(s). Environmental Toxicology published by Wiley Periodicals LLC.)

Our understanding of the gastrointestinal system in the pathophysiology of Parkinson’s disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and relaxation of smooth muscle and inflammation responses, by applying the serping1 siRNA were investigated in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD mice in an α-syn change aspect. In the result, serping1 expression was knocked down by the treatment of serping1 siRNA, and decreased serping1 induced the decrease α-syn in the colon. Furthermore, the changes in α-syn aggregation were also examined in the brain, and alleviated α-syn aggregation was also observed in an serping1 siRNA treatment group. The results indicated that serping1 siRNA could ease synucleinopathy related to the gastrointestinal system in PD. This study also raises the possibility that serping1 siRNA could alleviate α-syn aggregation in striatum and substantia nigra regions of the brain.

Background: Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe swellings of the skin and submucosa. More than 900 variants of the SERPING1 gene associated with HAE have been identified. However, only approximately 50 variants have been identified in the Chinese population. This study aimed to update the mutational spectrum in Chinese HAE patients and provide evidence for the accurate diagnosis of HAE. Methods: A total of 97 unrelated HAE patients were enrolled in the study. Sanger sequencing and multiple ligation-dependent probe amplification analysis were used to identify the variants in the SERPING1 gene. The variants were reviewed in a number of databases, including the Human Gene Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk/) and the Leiden Open Variation Database (LOVD, https://databases.lovd.nl/shared/variants/SERPING1). The American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria was used to determine the pathogenicity of the variants. Results: Of the 97 patients, 76 different variants were identified in 90 of them and no disease-causing variants were identified in the remaining 7 patients. Among the 76 variants, 35 variants were novel and submitted to ClinVar. Missense and in-frame variants were the most common variants (36.8%), followed by frameshift (28.9%), nonsense (14.5%), splice site (13.2%) variants, and gross deletions/duplications (6.6%). Conclusions: Our findings broaden the mutational spectrum of SERPING1 and provide evidence for accurate diagnosis and predictive genetic counseling. [ABSTRACT FROM AUTHOR]

• HAE-C1-INH is characterised by a highly variable clinical phenotype. • We identified 39 variants in 23 genes that have potential as genetic biomarkers. • CC2D2B gene (variant c.190A>G, rs17383738) is disease-modifying factor of HAE-C1-INH. • Based on LD, CCNJ and ZNF518A , might also be involved in the clinical variability. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A , and ZNF790). We selected variants in CC2D2B and PLCL1 , which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07‐14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare autosomal-dominant disease that is caused by a deficiency (type I) or dysfunction (type II) of the C1 inhibitor (C1-INH) due to a mutation in the SERPING1 gene, which codes for C1-INH. HAE with quantitatively and qualitatively normal C1-INH (type III) is often caused by a mutation in the F12 gene and no mutations in the SERPING1 gene and is a group of very rare diseases. The C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases vascular permeability and allows the flow of fluids into the extracellular space, resulting in angioedema. HAE clinically manifests with intermittent attacks of swelling of the subcutaneous tissue or submucosal layers of the respiratory and gastrointestinal tract. Young children are typically asymptomatic, and those affected by HAE usually present with symptoms in their early 20s. This article describes the case of very early onset of hereditary angioedema caused by C1-INH deficiency in a 2-year-old boy who experienced recurrent episodes of hand and abdominal angioedema not associated with urticaria or pruritus. His father suffered from severe HAE due to a de novo mutation of the SERPING1 gene. The same mutation of the SERPING1 gene was detected in his son at the age of 9-months prior to the occurrence of angioedema symptoms, during genetic family counseling. This paper advances the understanding of HAE and highlights the importance of genetic counseling of families with HAE to avoid late or inaccurate diagnosis and to initiate treatment on time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Staikuniene-Kozonis, Staikunaite, Gasiuniene and Sematonyte.)

Tuberculosis (TB) remains a highly contagious public health threat. Precise and prompt diagnosis and monitoring of treatment responses are urgently needed for clinics. To pursue novel and satisfied host blood-derived biomarkers, we streamlined a bioinformatic pipeline by integrating differentially expressed genes, a gene co-expression network, and short time-series analysis to mine the published transcriptomes derived from whole blood of TB patients in the GEO database, followed by validating the diagnostic performance of biomarkers in both independent datasets and blood samples of Chinese patients using quantitative real-time PCR (qRT-PCR). We found that four genes, namely UBE2L6 (Ubiquitin/ISG15-conjugating enzyme E2 L6), BATF2 (Basic leucine zipper transcriptional factor ATF-like), SERPING1 (Plasma protease C1 inhibitor), and VAMP5 (Vesicle-associated membrane protein 5), had high diagnostic value for active TB. The transcription levels of these four gene combinations can reach up to 88% sensitivity and 78% specificity (average) for the diagnosis of active TB; the highest sensitivity can achieve 100% by parallel of BATF2 and VAMP5, and the highest specificity can reach 89.5% through a combination of SERPIG1, UBE2L6, and VAMP5, which were significantly higher than 75.3% sensitivity and 69.1% specificity by T-SPOT.TB in the same patients. Quite unexpectedly, the gene set can assess the efficacy of anti-TB response and differentiate active TB from Latent TB infection. The data demonstrated these four biomarkers might have great potency and advantage over IGRAs in the diagnosis of TB.

Introduction: Prevention of attacks is a major goal in management of patients with hereditary angioedema (HAE). We aimed to investigate the effects of a systematic intervention for HAE patients. Methods: Thirty-three patients with HAE with C1-inhibitor deficiency, belonging to a single family, participated in a management program coordinated by an allergist/immunologist. Angioedema attacks before intervention were ascertained by interviews and emergency room charts and recorded prospectively by patients or caregivers after enrollment. Mean number of attacks/month was compared at 12 months preintervention and 8 and 14 months within intervention. Patient-reported outcome instruments were used to assess quality of life, including HAE Quality of Life (HAE-QoL) questionnaire, psychological conditions, and work impairment, at baseline and 8 and 14 months within intervention. Data were stored in REDCap platform and analyzed by adjusted Bayesian models of double Poisson regression. Results: Mean number of attacks/month significantly decreased (95% credible interval [CrI] excluding 0) from 1.15 preintervention to 0.25 and 0.23, 8 and 14 months within intervention, with mean decreases of −0.89 (95% CrI: −1.21 to −0.58) and −0.92 (95% CrI: −1.22 to −0.60), respectively. HAE-QoL scores showed mean total increases of 15.2 (95% CrI: 1.23–29.77) and 26 (95% CrI: 14.56–39.02) at 8 and 14 months within the study, as compared to baseline, revealing marked improvement in quality of life. Significant increase in role-emotional and reduction of depression, stress, and anxiety were observed at 14 months. Conclusion: A systematic approach integrating HAE-specific care with effective handling of psychological issues decreased the number of attacks and improved quality of life, targets for best practice in HAE. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare condition characterized by episodic local edema involving various organs, which can be life‐threatening in some cases. Among the three subtypes of the disease, HAE types I and II are known to be caused by heterozygous mutations in the SERPING1 gene encoding C1 inhibitor (C1INH). Although a number of mutations in the SERPING1 gene have been identified to date, the mechanisms how these mutations cause HAE are not completely understood. We herein performed detailed in vitro studies for a missense SERPING1 gene mutation p.S150F which we recently identified in a Japanese patient with HAE type I. We showed that the p.S150F‐mutant C1INH was stably expressed within the cultured cells, while it was not secreted into the medium at all. Furthermore, we demonstrated that the mutant C1INH significantly prevented secretion of wild‐type C1INH. Finally, the results suggested that the wild‐type protein was not only retained but also degraded within the cytoplasm through interacting with the mutant protein. Our study clearly revealed a dominant‐negative effect of the p.S150F‐mutant C1INH against the wild‐type C1INH. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains a highly contagious public health threat. Precise and prompt diagnosis and monitoring of treatment responses are urgently needed for clinics. To pursue novel and satisfied host blood-derived biomarkers, we streamlined a bioinformatic pipeline by integrating differentially expressed genes, a gene co-expression network, and short time-series analysis to mine the published transcriptomes derived from whole blood of TB patients in the GEO database, followed by validating the diagnostic performance of biomarkers in both independent datasets and blood samples of Chinese patients using quantitative real-time PCR (qRT-PCR). We found that four genes, namely UBE2L6 (Ubiquitin/ISG15-conjugating enzyme E2 L6), BATF2 (Basic leucine zipper transcriptional factor ATF-like), SERPING1 (Plasma protease C1 inhibitor), and VAMP5 (Vesicle-associated membrane protein 5), had high diagnostic value for active TB. The transcription levels of these four gene combinations can reach up to 88% sensitivity and 78% specificity (average) for the diagnosis of active TB; the highest sensitivity can achieve 100% by parallel of BATF2 and VAMP5, and the highest specificity can reach 89.5% through a combination of SERPIG1, UBE2L6, and VAMP5, which were significantly higher than 75.3% sensitivity and 69.1% specificity by T-SPOT.TB in the same patients. Quite unexpectedly, the gene set can assess the efficacy of anti-TB response and differentiate active TB from Latent TB infection. The data demonstrated these four biomarkers might have great potency and advantage over IGRAs in the diagnosis of TB. [ABSTRACT FROM AUTHOR]

L'angiœdème héréditaire (AOH) est une maladie rare, potentiellement grave. C'est une pathologie caractérisée par la survenue d'œdèmes sous-cutanés ou sous-muqueux récurrents, localisés, sans urticaire associée, durant entre vingt-quatre (24) et soixante-douze (72) heures. Il disparaît sans laisser de séquelles et peut récidiver. C'est une maladie autosomique dominante qui résulte d'une déficience héréditaire de la fonction inhibitrice C1. Le gène codant pour le C1-inh (SERPING 1) a été localisé sur le chromosome 11 (11q12-q13.1). Notre travail est une étude de cas clinique avec revue de la littérature à propos d'un cas d'angiœdème bradykinique héréditaire enregistré au service de dermato-allergologie de l'Hôpital national Amirou Boubacar Diallo de Niamey. Il s'agit d'une patiente âgée de 37 ans avec un antécédent de lupus érythémateux chronique référée du service de l'ORL pour un bilan allergologique d'un œdème de la face. Son histoire clinique rapporte plusieurs épisodes d'angiœdèmes du visage, des extrémités des membres survenant de façon sporadique et qui durent en moyenne 48 à 72 heures, parfois accompagnés de troubles digestifs et d'œdème de Quincke. Ses bilans sanguins et génétiques ont rapporté un déficit quantitatif et qualitatif en C1 inhibiteur, un taux abaissé du complément C4 et une mutation homozygote du gène SERPING1 qui ont permis de poser le diagnostic d'angiœdème bradykinique héréditaire type I. En conclusion, l'angiœdème bradykinique héréditaire est une maladie rare qui pourrait être sous-estimée à cause de sa méconnaissance par de nombreux praticiens. Le tableau clinique est souvent trompeur, la morbi-mortalité est liée à l'atteinte des voies aériennes supérieures et aux symptômes abdominaux. Le diagnostic repose sur l'exploration du système du complément. Hereditary angioedema (HAE) is a rare, potentially serious disease. It is a pathology characterized by the occurrence of recurrent, localized subcutaneous or submucosal edemas, without associated urticaria, lasting between twenty-four (24) and seventy-two (72) hours. It disappears without leaving behind and can reoffend. It is an autosomal dominant disease that results from a hereditary deficiency of C1 inhibitory function. The gene encoding C1-inh (SERPING 1) was located on chromosome 11 (11q12-q13.1). Our work is a clinical case study with review of the literature about a case of hereditary bradykinic angioedema registered in the Dermato-allergology department of the Amirou Boubacar Diallo National Hospital. The case report is a 37-year-old women with a history of chronic lupus erythematosus referred from the ORL department for an allergic assessment of facial edema. Her clinical history reports several episodes of angioedema of the face, extremities of the members occurring sporadically and which last on average 48 to 72 hours sometimes accompanied by digestive disorders and Quincke's edema. His blood and genetic tests reported a quantitative and qualitative deficit in C1 inhibitor, a lowered level of C4 complement and a homozygous mutation in the SERPING1 gene that led to the diagnosis of hereditary bradykinic angioedema type I. In conclusion, hereditary bradykinic angioedema is a rare disease that may be underestimated because of its lack of knowledge by many practitioners. The clinical picture is often misleading, morbimortality is linked to the involvement of the upper airways and abdominal attacks. The diagnosis is based on the exploration of the complement system. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare genetic disorder, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. The impairment underlying HAE could be a defect in C1-inhibitor activity, or in its serum concentration. Patients affected by HAE should be treated with on-demand or prophylactic drugs. Lifelong C1-inhibitor supplementation is sometimes required. In this review, we review the currently approved drugs for HAE due to C1-inhibitor defect and to describe those under research. In particular, we focused on the mechanisms of action, routes of administration, and efficacy of these therapies. A systematic review of the literature was performed using the PubMed database for original articles and clinical trials of HAE treatments from 2005 to 2019. The approved HAE treatments can minimize the risk of death, but they are not effective in complete healing from the disease. The new gene therapies seem to provide promising opportunities for the treatment of hereditary angioedema. However, there are still many unmet needs, including efficacy, route, and timing of administration.

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity.

Background: There is paucity of literature on long‐term follow‐up of patients with hereditary angioedema (HAE) from developing countries. Objective: This study was carried out to analyze the clinical manifestations, laboratory features, and genetic profile of 32 patients (21 male and 11 female) from 23 families diagnosed with HAE between January 1996 and December 2019. Methods: Data were retrieved from medical records of Paediatric Immunodeficiency Clinic, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Results: Median age at onset of symptoms was 6.25 years (range 1‐25 years), and median age at diagnosis was 12 years (range 2‐43 years). Serum complement C4 level was decreased in all patients. All patients had low C1‐esterase inhibitor (C1‐INH) quantitative level (type 1 HAE). SERPING1 gene sequencing could be carried out in 20 families. Of these, 11 were identified to have a pathogenic disease‐causing variant in the SERPING1 gene. While 2 of these families had a previously reported mutation, remaining 9 families had novel pathogenic variants in SERPING1 gene. Because of non‐availability of C1‐INH therapy in India, all patients were given long‐term prophylaxis (attenuated androgens or tranexamic acid (TA) or a combination of the 2). Life‐threatening episodes of laryngeal edema were managed with fresh‐frozen plasma (FPP) infusions. We recorded one disease‐related mortality in our cohort. This happened in spite of long‐term prophylaxis with stanozolol and TA. Conclusions: We report largest single‐center cohort of patients with HAE from India. Attenuated androgens, fibrinolytic agents, and FPP may be used for management of HAE in resource‐limited settings. [ABSTRACT FROM AUTHOR]

Inflammatory responses to the novel coronavirus SARS-CoV-2, which causes COVID-19, range from asymptomatic to severe. Here we present a follow-up analysis of a longitudinal study characterizing COVID-19 immune responses from a father and son with distinctly different clinical courses. The father required a lengthy hospital stay for severe symptoms, whereas his son had mild symptoms and no fever yet tested positive for SARS-CoV-2 for 29 days. Father and son, as well as another unrelated COVID-19 patient, displayed a robust increase of SERPING1, the transcript encoding C1 esterase inhibitor (C1–INH). We further bolstered this finding by incorporating a serum proteomics dataset and found that serum C1–INH was consistently increased in COVID-19 patients. C1–INH is a central regulator of the contact and complement systems, potentially linking COVID-19 to complement hyperactivation, fibrin clot formation, and immune depression. Furthermore, despite distinct clinical cases, significant parallels were observed in transcripts involved in interferon and B cell signaling. As symptoms were resolving, widespread decreases were seen in immune-related transcripts to levels below those of healthy controls. Our study provides insight into the immune responses of likely millions of people with extremely mild symptoms who may not be aware of their infection with SARS-CoV-2 and implies a potential for long-lasting consequences that could contribute to reinfection risk.

Antecedentes: El angioedema hereditario se encuentra clasificado como una inmunodeficiencia primaria del sistema de complemento, debido a que se caracteriza por la ausencia de C1 inhibidor esterasa y por edema periódico de cualquier región del cuerpo que involucre tejido blando. Objetivo: Caracterizar a los pacientes adultos con diagnóstico de angioedema hereditario atendidos en el Servicio de Alergología Clínica del Hospital México de la Caja Costarricense del Seguro Social. Métodos: Estudio observacional retrospectivo. Los datos fueron obtenidos de los expedientes clínicos de los pacientes con diagnóstico confirmado de angioedema hereditario que estaban en seguimiento en el Servicio de Alergología del Hospital México, Caja Costarricense del Seguro Social. Resultados: Se identificaron 14 pacientes, siete hombres y siete mujeres. El promedio de edad fue de 36.6 años. Las manifestaciones clínicas más frecuentes fueron edema de extremidades y dolor abdominal. Solo tres pacientes en algún momento durante su evolución presentaron edema laríngeo; 12 casos correspondieron a angioedema hereditario tipo I. Conclusión: Las características clínicas de todos los casos documentados correspondieron con las descritas para angioedema, aunque solo algunos pacientes contaban con historial de manifestaciones graves.

• Serping1 increase accompanied with dopaminergic cell death in MPTP mouse model. • Serping1 decrease by siRNA caused dopaminergic cell increase in SH-SY5Y. • Dopaminergic cell loss was inhibited by Serping1 siRNA in MPP + treated SH-SY5Y. • Serping1 may play a critical role in dopaminergic cell death in parkinsonism model. Parkinson's disease (PD) is a progressive neurodegenerative disease, which shows distinct manifestations such as significant loss of dopaminergic neurons in the substantia nigra (SN). Gene expression was analyzed in the SN of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), wherein downregulation of dopaminergic neurons occurred to examine the possible causes leading to the loss of dopaminergic neurons. In addition, a serine/cysteine protease inhibitor (Serping1) was studied as one of the genes that were prominently upregulated in mice chronically intoxicated with MPTP. Western blot analysis showed that, concomitant to the downregulation of dopaminergic cells, there was a substantial increase in Serping1 expression within the SN of the MPTP-induced PD mouse model. The SH-SY5Y cells were transfected with Serping1 short interfering RNA (siRNA) to evaluate the correlation between the expression of Serping1 and the loss of dopaminergic cells. Serping1 depletion elicited the upregulation of dopaminergic cells. Moreover, neuroprotective effect against dopaminergic cell loss was demonstrated upon the inhibition of Serping1 expression by siRNA in the MPP+ (1-methyl-4-phenylpyridinium)- treated SH-SY5Y cells. These results show that increased expression of Serping1 may play a critical role in dopaminergic cell death in the SN of chronic MPTP-induced PD mouse model and in SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) type I and II is a rare and life-threatening disease caused by SERPING1 gene mutations. Previous genetic studies indicated a wide spectrum of disease-associated variants in the SERPING1 gene and often lack of correlation with patient's phenotypes. The aim of this study was to evaluate the presence, type, and localization of mutations in the SERPING1 gene in 41 Polish patients with C1-INH-HAE and their relation with case/family history, type of C1-INH-HAE, fC1-INH, age of onset, and disease severity. Sanger sequencing and MLPA method were used for detection of disease-associated variants. In 34 (82.9%) patients, mutations located in various regions of SERPING1 gene were revealed. The detected alterations in patients with C1-INH-HAE type I differed and were positioned in various exons/introns of the SERPING1 gene. The most frequent disease-associated variants appeared in exon 3 (especially in type I) and in exon 8 (type I and II). Out of 20 different disease-causing variants, 9 were not previously described. We did not find any relation between the type and location of the mutations and no type of features included in phenotype evaluation of the patients, such as case and family history, type of C1-INH-HAE, age of onset, biochemical parameters, or severity of disease. [ABSTRACT FROM AUTHOR]

• SERPING1 expression was increased in patients with active tuberculosis. • C1-inhibitor proteins levels were increased in half of the TB cohorts analysed. • C1-inhibitor was not increased in other clinically relevant conditions. • C1-inhibitor levels normalised over the course of treatment. • A positive correlation between C1q and C1-inhibitor was found in TB patients. To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1 , which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema is classified as a primary immunodeficiency of the complement system because it is characterized by the absence of C1 esterase inhibitor (C1-INH) and by the periodic edema of any region of the body that involves soft tissue. Objective: To characterize the adult patients with a confirmed diagnosis of hereditary angioedema who have been treated in the Clinical Allergology Department of Hospital México de la Caja Costarricense del Seguro Social. Methods: The study was retrospective and observational. The information was obtained from the clinical records of the patients with a confirmed diagnosis of hereditary angioedema that were being controlled in the Allergology Department of the "Hospital México de la Caja Costarricense del Seguro Social". Results: A total of 14 patients; seven men and seven women, were identified. The average was of 36.6 years of age. The most frequent clinical manifestations were peripheral edema and abdominal pain. Only three patients presented laryngeal edema at some point in their evolution. 12 cases corresponded to hereditary angioedema type I. Conclusion: The clinical characteristics of all the documented cases corresponded to those described for this pathology, although only a few patients had a history of severe manifestations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema with deficient and dysfunctional C1 inhibitor (C1‐INH‐HAE) is a rare genetic disorder. The majority of the cases with this disease are caused by mutations in the C1‐inbitor gene SERPING1 and are classified as type 1 and type 2. We aimed to detect mutations in the SERPING1 gene and evaluate its expression in nine probands with hereditary angioedema from nine different families. Methods: Nine probands with hereditary angioedema from nine different families and 53 healthy controls were recruited in this study. All eight exons and intron–exon boundaries in the SERPING1 gene were amplified by PCR and then sequenced. Mutations were identified by alignment with reference sequences. mRNA expression was measured by real‐time PCR. Results: All probands were diagnosed with HAE type 1. Nine mutations were found in nine patients: c.44delT, c.289C

C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1‐INH‐HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein–kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin–protease association and a residual 105‐kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1‐INH‐HAE probands presented with an additional so‐called intermediate C1‐INH‐HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype–phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy. [ABSTRACT FROM AUTHOR]

Hereditary angioedema is a rare, potentially life-threatening disease. There is a lack of data describing the clinical course of hereditary angioedema (HAE) in children. We aimed to evaluate the clinical characteristics of pediatric patients with hereditary angioedema: The age of disease onset, age at diagnosis, the frequency of angioedema attacks, the total number of attacks before diagnosis, the regions where angioedema attacks were observed, accompanying abdominal pain, and serum levels of C4 and C1 esterase inhibitor were obtained and recorded. In addition, the results of SERPING1 (C1INH) gene sequence analysis of the patients in this group were also collected from medical records and recorded. While none of the patients reported a skin rash as a symptom of attack, there was formication observed in the region of angioedema in 46.9% (n = 15) of the patients and pruritus in 6.2% (n = 2) of the patients. At disease onset, the complaints of the patients regarding location of edema were on the hands of 32.3% (n = 10), on the feet of 9.7% (n = 3), on the faces of 25.7% (n = 8), and abdominal attacks in 32.3% of the patients (n = 10). Four different variants, one of which was novel, were detected in the SERPING1 gene in eight different families. The results of this study suggest that hereditary angioedema is diagnosed only when the patient requests examination following recurrent angioedema. Severe laryngeal edema attacks in patients without a diagnosis of HAE are fatal at a higher rate than attacks in patients with a diagnosis. Thus, awareness of the symptoms of HAE is necessary, and correct diagnosis is essential to proper treatment.

Variants that affect splice sites comprise 14.3% of all pathogenic variants in the SERPING1 gene; more than half of them are located outside the canonical sites. To make a clinical decision concerning patients with such variants, it is essential to know the exact way in which the effect of the variant would be realized. The optimal approach to determine the consequences is considered to be mRNA analysis. In the current study, we present the results of functional analysis of two previously non-described variants in the SERPING1 gene (NM_000062.3) affecting intron 4: c.686-1G>A and c.685+4dup, which were detected in members of two Russian families with autosomal dominant inheritance of angioedema type 1. Analysis of the patients' mRNA (extracted from whole blood) showed that the SERPING1 (NM_000062.3):c.685+4dup variant leads to the loss of the donor splice site and the activation of the cryptic site in exon 4: r.710_745del (p.Gly217_Pro228del), while the SERPING1 (NM_000062.3):c.686-1G>A variant leads to the skipping of exon 5: r.746_949del (p.Asp229_Ser296del).

Introduction: Hereditary angioedema (HAE) may be fatal and diagnosis can be delayed up to 10 years. We aimed to screen HAE in two villages based on an index case of HAE and to investigate for the mutation of the C1 esterase inhibitor (C1-INH) gene. Material and methods: A total of 124 people were screened in two villages. The frequency and severity of symptoms were scored. C4, C1-INH levels and C1-INH activity were measured. We investigated for mutations of the C1-INH gene. Results: Thirty-five cases of type I HAE and 7 cases of type II HAE were determined. Thirty-one (73.8%) patients diagnosed with HAE were 18 years old or younger. There was a positive correlation between C4 levels, C1-INH levels (p < 0.0001, r = 0.81), and C1-INH activity levels (p < 0.0001, r = 0.631) and between the age at diagnosis and severity score (p < 0.0001, r = 0.651). A positive correlation was found between the age at first symptom onset and C4 levels (p = 0.002, r = 0.774), and C1-INH levels (p = 0.006, r = 0.714). A marginally significant negative correlation was found between C1-INH activity levels and severity scores (p = 0.1, r = -0.515). We identified a novel heterozygous 1033G>T missense variant of the C1-INH gene, SERPING1, in patients with type I HAE. Conclusions: There are long delay periods in the diagnosis of HAE and when the index case is present, family screening may be very important and even life-saving, in particular, in paediatric patients without symptoms. Furthermore, the present study provides evidence to link a novel mutation, c.1033G>T, to the development of HAE in a large HAE family from Turkey. [ABSTRACT FROM AUTHOR]

Highlights • SERPING1 exon 3 is alternatively spliced. • Highly abundant exon3 skipping isoform is not degraded by NMD. • Newly identified isoforms -15 and +38 comprise appreciable proportion of all SERPING1 transcripts. • Close acceptor splice sites are tightly co-regulated. Abstract 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different hereditary angioedema–causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown. The aim was to describe trans -inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants. HeLa cells were transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localization were carried out. Our findings characterized functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into 5 different clusters, each containing variants sharing specific molecular characteristics. For all variants except 2, we found that coexpression of mutant and normal C1INH negatively affected the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci was detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH. We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative disease mechanisms. [ABSTRACT FROM AUTHOR]

The authors wish to make corrections to their article: Nicola S, Rolla G, Brussino L. Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research. Drugs in Context 2019; 8: 212605. DOI: 10.7573/dic.212605

AIM: To explore the association between the polymorphism rs2511989 in the classical pathway geneSERPING1(C1 inhibitor)and age-related macular degeneration(AMD).METHODS: A random-effect Meta-analysis was performed. An electronic search was done in CNKI, PubMed, the Cochrane Collaboration's Database, Embase, and the ISI Web of Knowledge. Odds ratios(OR)and their 95% confidence interval(CI)were calculated to assess the strength of association between SERPING1 rs2511989 polymorphism and AMD susceptibility. Heterogeneity, sensitivity analysis and publication bias were also tested.RESULTS: A total of 15 case-control studies with 8657 cases and 5393 controls were finally included in this Meta-analysis. There was no significant association between SERPING1 and AMD in all genetic models.(Dominant model: OR=0.960, 95%CI: 0.918-1.003, P=0.009; recessive model: OR=0.898, 95%CI: 0.791-1.019, P=0.035; homozygote model: OR=0.881, 95%CI: 0.770-1.008, P=0.003; heterozygote model: OR=0.962, 95%CI: 0.917-1.010, P=0.050). However, the associations between SERPING1 and neovascular AMD were significant in three models(dominant model: OR=0.691, 95%CI: 0.547-0.872; homozygote model: OR=0.661, 95%CI: 0.450-0.971; heterozygote model: OR=0.754, 95%CI: 0.589-0.964). Subgroup analysis by ethnicity and country did not find significant association between rs2511989 polymorphism and AMD susceptibility.CONCLUSION: SERPING1 rs2511989 does not associates with AMD generally but may associate with neovascular AMD. More studies are required to verify the hypothesis.

AIM: To investigate the association between SERPING1 rs2511989 (G>A) polymorphism and age-related macular degeneration (AMD). METHODS: A number of electronic databases (up to July 15, 2014) were searched independently by two investigators. A Meta-analysis was performed on the association between SERPING1 rs2511989 polymorphism and AMD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: Eight studies with 16 cohorts consisting of 9163 cases and 6813 controls were included in this Meta-analysis. There was no significant association between rs2511989 polymorphism and AMD under all genetic models in overall estimates (A vs G: OR= 0.938, 95%CI =0.858-1.025; AA vs GG:OR =0.871, 95%CI =0.719-1.056; AG vs GG: OR =0.944, 95%CI =0.845-1.054; AA+AG vs GG: OR =0.927, 95% CI =0.823-1.044; AA vs AG+GG: OR =0.890, 95%CI =0.780-1.034). Cumulative Meta-analyses also showed a trend of no association between rs2511989 polymorphism and AMD as information accumulated by year. Subgroup analysis and Meta-regression analysis indicated that age-matching status was the main source of heterogeneity. Sensitivity analysis found the results in overall comparisons and subgroup comparisons of white subjects under the allele model were found to have significantly statistical differences after studies deviating from Hardy-Weinberg equilibrium (HWE) were excluded (overall: OR=0.918, 95%CI = 0.844-0.999, P =0.049; whites: OR =0.901, 95%CI = 0.817-0.994, P =0.038). However, the results were not sufficiently robust for further sensitivity analysis and statistical differences disappeared on applying Bonferroni correction (with a significance level set at 0.05/25). CONCLUSION: This Meta-analysis indicates that SERPING1 rs2511989 polymorphism and AMD tend to have no association with each other. Age matching status is a big confounding factor, and more studies with subtle designs are warranted in future.

Objective: The HIV-1 virus activates the complement system, an essential element of the immune system. SERPING1 is a protease inhibitor that disables C1r/C1s in the C1 complex of the classical complement pathway. Methods: In this paper, we performed an analysis of several microarrays deposited in GEO dataset to demonstrate that SERPING1 mRNA is modulated in CD14 monocytes from HIV-1-infected individuals. In addition, data were validated on monocytes isolated from seronegative healthy volunteers, treated with IFNs. Results: Our analysis shows that SERPING1 mRNA is overexpressed in monocytes from HIV-1+ patients and the expression levels correlate positively with viral load and negatively with the CD4 T-cell count. Of note, anti-retroviral therapy is able to reduce the levels of SERPING1 mRNA, ex vivo. In addition, we found that 30% of the SERPING1 genes network is upregulated in monocytes from HIV-1+ patients. Noteworthy, the expression levels of IFITM1-an antiviral molecule belonging to the genes network-correlate positively with SERPING1 expression. Interestingly, the monocytes treatment with IFN-gamma, IFN-beta and IFN-alpha significantly upregulates the SERPING1 mRNA expression levels. Conclusions: From the outcome of our investigation, it is possible to conclude that SERPING1 and its network serve as important components of the innate immune system to restrict HIV-1 infection. [ABSTRACT FROM AUTHOR]