Assessing the impact of a rare synonymous variant in the KNG1 gene on the development of hereditary angioedema

The main cause of edema in hereditary angioedema (HAE) is due to elevated bradykinin levels, caused either by C1-INH deficiency/change in functional activity and caused by mutations in the SERPING1 gene or by mutations in the F12, PLG, ANGPT1, KNG1, MYOF and HS3ST6 genes with a normal level and functionality of the C1-esterase inhibitor. The aim of the work was in silico prognostic analysis of the rare synonymous variant NC_000003.12:g.186725098T>C in the KNG1 gene and its impact on the development of HAE symptoms. The material was a whole blood sample obtained from a woman with clinical manifestations of hereditary angioedema without a decrease in the levels and function of the C1 inhibitor. The research methods included whole exome sequencing, bioinformatic analysis of the KNG1 gene mutation using a number of databases and web resources. Results. When processing full-exome sequencing data, we detected a synonymous variant in the KNG1 gene (exon 4, isoform 1): NC_000003.12:g.186725098T>C. The patient is a heterozygous carrier of the variant, with a frequency of 0.000004 (1:264690). Presumably, the identified variant can lead to the development of sporadic edema through several pathways that are associated with the formation of bradykinin or its analogues. Therefore, (1) the mutant high-molecular-weight kininogen is more easily activated by kallikrein and becomes a source of bradykinin formation through the kallikrein-kinin system; (2) the mechanism of bradykinin formation undergoes significant changes and results in the formation of functionally active but aberrant bradykinin, which alters its inactivation by enzymes with a consequent increase in its half-life, (3) the changes in positions 380-389 bring about modifications in Lys-bradykinin reproduction such that in subsequent steps it is “easily” cleaved to bradykinin by arginine aminopeptidase. The results of our study therefore indicate a possible role of the identified variant in the KNG1 gene in the development of HAE.

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