Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency

Denis Vincent; Faidra Parsopoulou; Ludovic Martin; Christine Gaboriaud; Jacques Demongeot; Gedeon Loules; Sascha Fischer; Sven Cichon; Anastasios E Germenis; Arije Ghannam; Christian Drouet

doi:10.1016/j.jacig.2024.100223

Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency

J Allergy Clin Immunol Glob. 2024 Feb 1;3(2):100223. doi: 10.1016/j.jacig.2024.100223. eCollection 2024 May.

Authors

Denis Vincent^{1

2}, Faidra Parsopoulou^{3

4}, Ludovic Martin^{5

6}, Christine Gaboriaud⁷, Jacques Demongeot⁸, Gedeon Loules⁴, Sascha Fischer^{9

10}, Sven Cichon^{9

10}, Anastasios E Germenis¹¹, Arije Ghannam³, Christian Drouet^{8

12}

Affiliations

¹ Allergy and Internal Medicine Unit, University Hospital, Nîmes, France.
² Centre de compétence, Centre de Référence des Angioedèmes (CREAK), Nîmes.
³ KininX SAS, Grenoble, France.
⁴ CeMIA SA, Larissa, Greece.
⁵ Dermatology Department, University Hospital, Angers, France.
⁶ Centre de Référence des Maladies Rares de la peau et des muqueuses d'origine génétique-Nord (MAGEC), filière FIMARAD, CHU Angers, Angers, France.
⁷ Université Grenoble Alpes, CEA, CNRS, IBS, Grenoble, France.
⁸ Université Grenoble Alpes, CHU Grenoble Alpes, Grenoble, France.
⁹ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
¹⁰ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
¹¹ Department of Immunology and Histocompatibility, University of Thessaly, Larissa, Greece.
¹² Institut Cochin, INSERM, CNRS, Université Paris Cité, 75679, Paris, France.

Abstract

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 underdiagnosed 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 sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency.

Methods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and 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 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: 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 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.

Keywords: CPN1 gene; Urticaria; angioedema; hereditary carboxypeptidase N deficiency.