SERPING1 – Hereditary angioedema

Hereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant disorder caused by pathogenic variants in the SERPING1 gene, encoding C1-esterase inhibitor (C1-INH). Affected individuals present with recurrent, non-pruritic, non-pitting edema of the skin and submucosa, and attacks may involve the upper airway or gastrointestinal tract, leading to laryngeal obstruction or severe abdominal pain ([PMID:1518394]). Functional C1-INH deficiency permits unchecked activation of the kallikrein-kinin system, increasing bradykinin generation and vascular permeability.

Genetic studies in 226 unrelated patients from 80 families demonstrate the broad allelic heterogeneity of SERPING1, with >200 unique variants reported, including missense, nonsense, frameshift, splice site, and large exon deletions ([PMID:1518394]; [PMID:11112899]). Approximately 25–33% of HAE cases are sporadic, due to de novo point mutations or microdeletions in SERPING1 ([PMID:11112899]). Segregation analyses confirm autosomal dominant transmission in multigenerational pedigrees, with complete cosegregation of loss-of-function variants and disease phenotype.

Case reports and series encompass over 200 probands harboring heterozygous SERPING1 variants leading to type I (quantitative deficiency) or type II (functional defect) HAE. Recurrent founder and hotspot mutations, such as splice-site changes (c.51+3A>G) and point mutations generating premature stop codons, account for multiple independent families. A representative pathogenic variant is c.301C>T (p.Gln101Ter), which introduces a premature termination codon, abrogating C1-INH secretion and function.

Functional assays, including minigene splicing analyses and mRNA quantification, have demonstrated exon skipping and pseudoexon activation for intronic and splice-site variants (e.g., c.51+3A>G) leading to unstable transcripts and reduced C1-INH levels ([PMID:16470590]; [PMID:31982983]). In vitro studies of mutant C1-INH confirm intracellular retention or degradation, supporting haploinsufficiency as the primary mechanism. A clinical rescue case with normalization of C1-INH levels after liver transplantation further validates the hepatic origin of C1-INH and the reversibility of deficiency ([PMID:38959481]).

No credible conflicting evidence has been reported disputing the causal role of SERPING1 in HAE. Rare reports of HAE-like angioedema with normal C1-INH direct attention to F12 or other genes but do not undermine the SERPING1–HAE association. Ongoing detection of deep intronic and regulatory variants underscores the need for comprehensive sequencing in unresolved cases.

Taken together, genetic and functional data establish a definitive causal relationship between SERPING1 variants and hereditary angioedema. Genetic testing of SERPING1 allows accurate diagnosis, guides prophylaxis and on-demand therapy, and informs family counseling. Key take-home: early recognition of SERPING1-mediated HAE enables life-saving interventions and precision management.

References

• Medicine • 1992 • Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients PMID:1518394
• Journal of Allergy and Clinical Immunology • 2000 • Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema PMID:11112899
• 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 New England Journal of Medicine • 2024 • Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema PMID:38959481

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