Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 1;3(2):100223.
doi: 10.1016/j.jacig.2024.100223. eCollection 2024 May.

Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency

Denis Vincent  1   2 , Faidra Parsopoulou  3   4 , Ludovic Martin  5   6 , Christine Gaboriaud  7 , Jacques Demongeot  8 , Gedeon Loules  4 , Sascha Fischer  9   10 , Sven Cichon  9   10 , Anastasios E Germenis  11 , Arije Ghannam  3 , Christian Drouet  8   12
Affiliations

Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency

Denis Vincent et al. J Allergy Clin Immunol Glob. .

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] J Allergy Clin Immunol Glob. 2024 Aug 2;3(4):100319. doi: 10.1016/j.jacig.2024.100319. eCollection 2024 Nov. J Allergy Clin Immunol Glob. 2024. PMID: 39239323 Free PMC article.

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.

PubMed Disclaimer

Conflict of interest statement

This work was supported by an 10.13039/100017732E-Rare-1 research grant attributed within European FP7 (HAEIII; S. Cichon, coordinator) and a French National Agency for Research grant (grant no. EudraCT #38RC09.023). The promoter for the study was CHU Grenoble Alpes (#2009-A00025-52). Funding was also obtained from the French National Blood Service (Etablissement Français du Sang) La Plaine Saint Denis (grant no. APR2016-64), from KininX SAS, and the National Rare Disease Program from the French Ministry of Health (National Reference Center for Angioedema CREAK). F.P. was recipient of a PhD fellowship from Etablissement Français du Sang (#APR2016-64). Disclosure of potential conflict of interest: F. Parsopoulou, G. Loules, and A. Ghannam received grants as stated in the funding section. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

Fig 1
Fig 1
Pedigrees of families A-D presenting with a CPN deficiency. Results of next-generation sequencing and Sanger sequencing analyses. The CPN1 variants c.533G/A, c.582G/A, c.734C>T, and c.1299C>T and additional variants cosegregating with clinical symptoms are presented. Filled symbol: individual affected by recurrent angioedema possibly associated with urticarial lesions; empty symbol: asymptomatic subject; dashed symbol: noninvestigated family member. Arrows indicate the probands of investigated families.
Fig 2
Fig 2
Expanded view of the CPN 3-dimensional structure (PDB #2NSM) showing the position of CPN1 variants described in the study. The catalytic triad is labeled red, and the catalytic Zn2+-binding site is indicated in blue. Residues lining the Arg/Lys binding pocket are labeled red, and the Zn2+-binding and catalytic residues are colored blue. Residues are numbered according to positions in the mature protein.
See this image and copyright information in PMC

References

    1. Sharma J., Jindal A.K., Banday A.Z., Kaur A., Rawat A., Singh S., et al. Pathophysiology of hereditary angioedema (HAE) beyond the SERPING1 gene. Clin Rev Allergy Immunol. 2021;60:305–315. - PubMed
    1. Zanichelli A., Longhurst H.J., Maurer M., Bouillet L., Aberer W., Fabien V., et al. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016;117:394–398. - PubMed
    1. Dewald G., Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006;343:1286–1289. - PubMed
    1. Cichon S., Martin L., Hennies H.C., Müller F., Van Driessche K., Karpushova A., et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006;79:1098–1104. - PMC - PubMed
    1. Bork K., Wulff K., Steinmüller-Magin L., Braenne I., Staubach-Renz P., Witzke G., et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018;73:442–450. - PubMed