Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

Ren, Zhaoyu; Zhao, Shuang‐Xia; Li, Tiandao; Wedner, H. James; Atkinson, John P.

doi:10.1016/j.jaci.2022.11.027

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…This variant fits into a small series of recessive variants that are distributed across the complete SERPING1 gene (Figure S1). Previous studies have reported eight families with homozygous or compound heterozygous probands and an unambiguous recessive form of HAE-C1-INH [10,[24][25][26][27][28][29][30][31] (Table S2). The recurrent variant c.1198C>T (p.Arg400Cys), rs201363394, which was identified in five kindreds, actually appears to be a dominant variant, because several symptomatic heterozygous carriers were identified [8,[36][37][38].…”

Section: Discussionmentioning

confidence: 99%

“…Distribution of the reported recessive variants in the SERPING1 gene according to their mature protein numbering. The reference [8,10,[24][25][26][27][28][29][30][31][32][33][36][37][38][39][44][45][46][47] are cited in Supplementary Materials. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…Approximately 6% of the variants occur de novo [10]. In contrast with a large spectrum of dominant variants, only very few recessive forms of HAE-C1-INH have been described in a limited number of families [10,[24][25][26][27][28][29][30][31]. All the recessive variants are located in exonic regions and result in HAE-1 in the majority of patients.…”

Section: Introductionmentioning

confidence: 99%

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Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema

Maia,

Burger,

Ghannam

et al. 2023

JCM

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema

Maia,

Burger,

Ghannam

et al. 2023

JCM

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“…Genome sequencing for three unsolved patients revealed a previously-missed pathogenic variant, illustrating genome sequencing's capacity to resolve challenging cases. Similarly Ren et al [21] was able to solve all cases with HAE-I or HAE-II using genome sequencing for the initially-"negative" cases. Notably, the absence of pathogenic variants in two patients, despite extensive analysis, prompted a re-evaluation of their diagnoses; the emergence of paraproteins in one patient led to a revised diagnosis of histaminergic AE, while another patient's symptoms resolved and their C1 activity normalised.…”

Section: Genetic Testing Of All Currently Known Hae (Candidate) Genes...mentioning

confidence: 99%

Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients

Rozevska,

Kanepa,

Purina

et al. 2024

Allergy Asthma Clin Immunol

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Hereditary angioedema (HAE) poses diagnostic challenges due to its episodic, non-specific symptoms and overlapping conditions. This study focuses on the genetic basis of HAE, particularly focusing on unresolved cases and those with normal C1-inhibitor levels (nC1-INH HAE). This study reveals that conventional testing identified pathogenic variants in only 10 patients (n = 32), emphasizing the necessity for an integrative approach using genome, exome, and transcriptome sequencing. Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21). Investigation into candidate genes yielded no pathogenic variants, prompting a re-evaluation of patients’ diagnoses. This study advocates for a nuanced approach to genetic testing, recognizing its limitations and emphasizing the need for continuous clinical assessment. The complex genetic landscape of nC1-INH HAE necessitates further research for a more comprehensive understanding. In conclusion, this study contributes valuable insights into the genetic intricacies of HAE, highlighting the challenges in diagnosis and the evolving nature of the disease. The findings underscore the importance of advanced sequencing techniques and an integrated diagnostic strategy in unravelling the complexities of HAE, particularly in nС1-INH HAE cases.

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Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort

Grombirikova,

Bily,

Soucek

et al. 2023

J Clin Immunol

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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.

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Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

Cited by 9 publications

References 44 publications

Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema

Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema

Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients

Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort

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