SERPING1 – Hereditary Angioedema Type I

Hereditary angioedema type I (HAE1) is an autosomal dominant disorder caused by quantitative deficiency of the C1 esterase inhibitor (C1-INH), encoded by SERPING1, leading to recurrent angioedema (MONDO:0015053). Clinically, patients present with episodic subcutaneous and submucosal swelling, abdominal pain, and dizziness due to uncontrolled bradykinin release (PMID:22882460).

HAE1 follows autosomal dominant inheritance. Numerous heterozygous pathogenic variants in SERPING1 have been described. In a large Chinese family, the novel frameshift variant c.1391-1445del55 (p.Val464fsTer556) abolishing the stop codon in exon 8 segregated with low C1-INH and C4 levels in seven affected members (PMID:22882460). A de novo missense in exon 4 was reported in a sporadic patient with recurrent abdominal pain (PMID:27725554).

Multi-family studies further confirm genetic heterogeneity. A Colombian cluster includes four unrelated pedigrees with 79 affected individuals; segregation analysis in 44 members validated causative variants c.1417G>A (p.Val473Met), c.1420C>T (p.Tyr423Ter), and c.1238T>G (p.Met413Arg) (PMID:39724085). Czech national screening of 207 patients from 85 families detected causal variants in all but one family, highlighting a high prevalence of splicing defects.

The variant spectrum exceeds 900 unique alleles, encompassing missense, nonsense, frameshift, canonical splice-site, deep intronic, and large deletions. The recurrent nonsense c.1420C>T (p.Tyr423Ter) is reported across multiple populations. Segregation in extended pedigrees (44 individuals) confirms co-segregation with disease (PMID:39724085).

Functional assays demonstrate pathogenic mechanisms. Splice-site mutations c.51+3A>G and c.51+5G>A cause exon 2 skipping in minigene assays and cosegregate with low C1-INH levels (PMID:16470590). The deep intronic c.1029+384A>G activates a pseudoexon leading to nonsense-mediated decay (PMID:31982983). The p.Ser150Phe missense variant exerts dominant-negative effects by trapping wild-type C1-INH intracellularly (PMID:33914953). Recombinant expression of p.Pro399Ala and p.Cys130Trp variants shows impaired folding and secretion (PMID:36587848).

Collectively, genetic and experimental concordance across diverse cohorts establish a definitive association between SERPING1 and HAE1. Pathogenic variants disrupt C1-INH secretion or function via haploinsufficiency and dominant-negative effects, underpinning bradykinin-mediated angioedema. SERPING1 variant analysis is clinically actionable for diagnosis, family counseling, and personalized management in HAE1.

References

• Experimental Dermatology • 2012 • A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I. PMID:22882460
• Human Mutation • 2006 • Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH. PMID:16470590
• Journal of Clinical Immunology • 2020 • Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation. PMID:31982983
• The Journal of Dermatology • 2021 • Evidence for a dominant-negative effect of a missense mutation in the SERPING1 gene responsible for hereditary angioedema type I. PMID:33914953
• The Journal of Allergy and Clinical Immunology • 2023 • Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses. PMID:36587848
• — • 2025 • Concise abstract of the association.

Evidence Based Scoring (AI generated)