SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes.

Area of Science:

• Genetics
• Biochemistry
• Immunology

Background:

• C1 inhibitor (C1Inh) deficiency causes hereditary angioedema (C1-INH-HAE).
• C1Inh regulates the kallikrein-kinin system, controlling bradykinin generation.
• SERPING1 gene variants are the primary cause of C1Inh deficiency.

Purpose of the Study:

• To comprehensively document SERPING1 variants and their associated C1-INH-HAE phenotypes.
• To identify functionally important residues within C1Inh related to serpin activity.
• To advance the understanding of C1Inh deficiency as a serpinopathy.

Main Methods:

• Systematic documentation of published and novel SERPING1 variants.
• Analysis of variant types including heterozygous, homozygous, and compound heterozygous.
• Phenotypic analysis of C1Inh function and correlation with identified variants.

Main Results:

• A total of 748 SERPING1 variants are documented, including 120 novel ones.
• Variants were identified as heterozygous, homozygous, and compound heterozygous, with some cases of de novo and gonadal mosaicism.
• Functional analysis revealed dysfunctional serpin variants and identified an intermediate C1-INH-HAE phenotype in 74 probands.

Conclusions:

• The comprehensive SERPING1 variant spectrum facilitates genotype-phenotype correlations in C1-INH-HAE.
• Key residues critical for serpin function were highlighted, advancing the understanding of C1Inh's 'mousetrap' mechanism.
• This work refines the classification of C1Inh deficiency as a serpinopathy, improving diagnostic and therapeutic strategies.