SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE.

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is a rare genetic disorder.
• C1 Inhibitor (C1-INH) is crucial for regulating the kallikrein-kinin system (KKS) and controlling inflammation via complement and plasminogen pathways.
• Dysregulation of these systems due to C1-INH deficiency leads to recurrent swelling episodes.

Purpose of the Study:

• To analyze the spectrum and characteristics of SERPING1 gene variants in C1-INH-HAE patients.
• To understand the genetic basis and pathogenic mechanisms of C1-INH-HAE.
• To provide insights into genotype-phenotype correlations and diagnostic criteria.

Main Methods:

• Bioinformatic analysis of SERPING1 variants from a large cohort (n=809) and pedigrees (n=1,494).
• Classification of variants based on pathogenicity (pathogenic, likely pathogenic, benign, etc.).
• Analysis of variant types including deletions, duplications, missense, and splice site mutations.
• Investigation of de novo variants and gonadal mosaicism.

Main Results:

• SERPING1 variants account for 86.8% of HAE families, with a high mutational liability.
• Over 90% of reported SERPING1 variants are pathogenic or likely pathogenic.
• Common mechanisms include haploinsufficiency, dominant-negative effects, deletions/duplications (especially in exon 4), and splice site alterations.
• De novo variants represent 5.6% of cases; gonadal mosaicism is rare.

Conclusions:

• SERPING1 variants are the primary cause of C1-INH-HAE, exhibiting diverse mutation types.
• Haploinsufficiency and dominant-negative effects are key pathogenic mechanisms.
• Accurate genetic diagnosis requires correlating SERPING1 genotypes with clinical and biological findings, identifying potential serpinopathies.