Abstract
BackgroundHereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 Inhibitor (HAE-nC1-INH) is an under-diagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood. ObjectiveWe investigated the biological parameters and the genes related to kallikrein-kinin system (KKS) in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency. MethodsThis study includes four families presenting with HAE-nC1-INH and CPN deficiency. Patients’ clinical records were examined, biological parameters of KKS measured, genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (HSF®, SIFT®, Polyphen-2®, MutationTaster®, ClinPred®) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing. ResultsPatients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity –30 to 50% of median value in plasma. We identified three variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN at: c.533G>A, c.582A>G and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members. ConclusionsCPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in four unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxins accumulation, with synergistic effects in angioedema and urticarial symptoms.
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More From: The journal of allergy and clinical immunology. Global
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