SERPING1 – C1 inhibitor deficiency

SERPING1 encodes the C1 esterase inhibitor (C1-INH), a serine protease inhibitor that regulates complement and kallikrein-kinin pathways. Heterozygous pathogenic variants in SERPING1 cause autosomal dominant C1 inhibitor deficiency, clinically presenting as episodic subcutaneous (HP:0001030), mucosal (HP:0000979), and visceral edema (HP:0001826), known as hereditary angioedema type I and II.

In a Danish cohort, 59 probands (PMID:20804470) and 33 additional affected relatives across 26 families (PMID:20804470) were characterized, revealing 13 novel and over 200 total SERPING1 variants. Segregation of the splice mutation c.51+3A>G with decreased C1-INH levels in one family (PMID:16470590) further supports pathogenicity. The common polymorphism c.-21T>C does not affect clinical severity (PMID:20804470).

The mutational spectrum includes missense (e.g., c.550G>A (p.Gly184Arg)), nonsense, frameshift, canonical splice, and deep intronic variants. Carrier frequency is very low (<0.2%), consistent with disease prevalence. No definitive genotype–phenotype correlation exists, though null alleles often lead to earlier onset and more severe attacks.

Functional assays demonstrate loss‐of‐function and dominant‐negative mechanisms. For example, the p.Ser150Phe missense mutant is retained intracellularly and inhibits wild‐type secretion, confirming a dominant‐negative effect (PMID:33914953). Splice‐site variants such as c.51+5G>A induce exon skipping in minigene assays (PMID:16470590).

No credible conflicting evidence disputes the SERPING1–C1 inhibitor deficiency relationship. Alternative phenotypes have not been attributed to heterozygous SERPING1 variants.

In summary, extensive genetic and experimental evidence establishes a definitive association between SERPING1 variants and autosomal dominant C1 inhibitor deficiency. Genetic testing of SERPING1 enables precise diagnosis, informs prognosis, and guides personalized prophylaxis and therapy.

Key Take-home: Heterozygous SERPING1 variants are definitively linked to autosomal dominant C1 inhibitor deficiency; comprehensive genetic and functional assessment underpins clinical management.

References

• Allergy • 2011 • Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. PMID:20804470
• Human mutation • 2006 • Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH. PMID:16470590
• Molecular immunology • 2006 • Characterisation of a new C1 inhibitor mutant in a patient with hepatocellular carcinoma. PMID:16529817
• 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

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