Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency–causing KNG1 variants, and estimated prevalence

Adenaeuer, Anke; Trinchero, Alice; Krutmann, Sarah; Nazir, Hanan; Ambaglio, Chiara; Rocco, Vincenzo; Pancione, Ylenia; Tomao, Luigi; Ruiz-Sáez, Arlette; Echenagucia, Marión; Alesci, S.; Sollfrank, Stefanie; Ezigbo, Eyiuche D.; Häuser, Friederike; Lackner, Karl J.; Lämmle, Bernhard; Rossmann, Heidi

doi:10.1016/j.jtha.2022.11.011

Cited by 5 publications

(1 citation statement)

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“…KNG1 is also a protease inhibitor involved in the blood coagulation process. Gene mutations of KNG1 can cause a rare type of HAE with a normal C1-INH level [33,35]. Furthermore, urinary CLU expression was signi cantly correlated with HAE severity.…”

Section: Discussionmentioning

confidence: 99%

Uncovering Urinary Protein Biomarkers for Early Diagnosis and Evaluation of Hereditary Angioedema

Wu,

Tang,

Zhou

et al. 2024

Preprint

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Purpose Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. Noninvasive and disease-specific biomarkers are needed for the early diagnosis and disease evaluation of HAE. We aimed to explore and identify urinary protein biomarkers of HAE in healthy controls (HCs) or disease-control patients. Methods Using data-independent acquisition (DIA) based urinary proteomics, differentially expressed proteins were identified between HAE and HC groups. Functional annotation of differentially expressed proteins was performed using Ingenuity pathway analysis. Then, the parallel reaction monitoring (PRM) targeted proteomics method was used in validation cohort 1 to validate some promising biomarker candidates. Furthermore, enzyme-linked immunosorbent assays (ELISA) were conducted in validation cohort 2 to verify pro-epidermal growth factor (EGF), C1 esterase inhibitor (C1-INH), and kininogen-1 (KNG1) levels. Results Among the 2562 urinary proteins identified, 269 showed differential expression between HAE and HC. The differentially expressed proteins were significantly enriched in phospholipase C signaling, coagulation system, acute phase response signaling, leukocyte extravasation signaling, and actin cytoskeleton signaling. In the biofunction analysis, these differential proteins were significantly enriched in leukocyte migration, adhesion of immune cells, endothelial cell development, permeability of the vascular system, and cell death of immune cells. Moreover, urinary clusterin level was significantly correlated with disease severity scores of HAE (R = -0.758, p < 0.01). A urinary biomarker panel (C1-INH, EGF, and KNG1) was validated in two independent clinical cohorts with area under the curve (AUC) values of 0.910 and 0.949 for HAE diagnosis. Conclusions This study describes the first application of a DIA-PRM-ELISA workflow to identify and validate noninvasive and HAE-specific biomarkers in urine. These findings will contribute to the pathogenesis research and biomarker discovery of HAE.

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Section: Discussionmentioning

confidence: 99%