Hereditary angioedema with normal C1 Inhibitor associated with Carboxypeptidase N deficiency
Résumé
Background: Hereditary 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.
Objective: We 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.
Methods: This 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.
Results: Patients 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.
Conclusions: CPN1 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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