GENERAL COMMENTARY published: 03 April 2020 doi: 10.3389/fgene.2020.00304 Commentary: Bradykinin-Mediated Angioedema: An Update of the Genetic Causes and the Impact of Genomics Roger Colobran 1,2,3* 1 Immunology Division, Department of Cell Biology, Physiology and Immunology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain, 2 Department of Clinical and Molecular Genetics, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 3 Jeffrey Model Foundation Excellence Center, Barcelona, Spain Keywords: hereditary angioedema, plasminogen, mutation, HGVS nomenclature, genetic variant A Commentary on Bradykinin-Mediated Angioedema: An Update of the Genetic Causes and the Impact of Genomics by Marcelino-Rodriguez, I., Callero, A., Mendoza-Alvarez, A., Perez-Rodriguez, E., Barrios-Recio, J., Garcia-Robaina, J. C., et al. (2019). Front. Genet. 10:900. doi: 10.3389/fgene.2019.00900 Hereditary angioedema (HAE) is a rare autosomal-dominant genetic disease characterized by recurrent episodes of edema of the deep dermis and mucosal/submucosal tissues, and less Edited by: Anastasios E. Germenis, frequently, potentially life-threatening laryngeal edema. The estimated worldwide prevalence of University of Thessaly, Greece HAE is 1:50,000, but this figure may be even higher, as patients with this condition are often misdiagnosed or undiagnosed (Bernstein, 2018). The genetic bases of HAE were initially associated Reviewed by: Camila Lopes Veronez, with mutations in SERPING1, the gene that encodes the C1-inhibitor (C1-INH) protein. In the University of California, San Diego, absence of adequate functional C1-INH, the plasma contact system is insufficiently regulated, with United States consequent generation of bradykinin, the primary mediator of swelling in HAE. Now, more than *Correspondence: 20 years since this genetic cause was identified (Bissler et al., 1997), the latest update includes Roger Colobran 748 different SERPING1 variants associated with HAE (Ponard et al., 2019). Nonetheless, in rcolobran@vhebron.net addition SERPING1, which still accounts for the majority of genetic defects underlying HAE, an increasing number of new causal genes have been identified, especially in the last few years. The Specialty section: genes that cause HAE in patients with normal C1-INH levels are coagulation factor 12 gene (F12) This article was submitted to (discovered in 2006) (Dewald and Bork, 2006), angiopoietin-1 (ANGPT1) and plasminogen gene Genomic Medicine, (PLG) (discovered in 2018) (Bafunno et al., 2018; Bork et al., 2018b), and kininogen-1 gene (KNG1) a section of the journal (discovered in 2019) (Bork et al., 2019). Frontiers in Genetics I read with great interest the article by Marcelino-Rodriguez et al. on the genetic Received: 16 January 2020 causes of bradykinin-mediated angioedema (Marcelino-Rodriguez et al., 2019). These authors Accepted: 13 March 2020 comprehensively reviewed all HAE causal genes, including those most recently described, and Published: 03 April 2020 emphasized the crucial role of next generation sequencing (NGS), specifically whole-exome Citation: sequencing (WES), in these recent discoveries. When they dealt with PLG, one of the recently Colobran R (2020) Commentary: Bradykinin-Mediated Angioedema: An described HAE causal genes, they focused on the p.Lys330Glu mutation, a recurrent mutation Update of the Genetic Causes and the described in more than 20 independent families from different European countries and Japan Impact of Genomics. (Belbézier et al., 2018; Bork et al., 2018b; Germenis et al., 2018; Yakushiji et al., 2018; Recke et al., Front. Genet. 11:304. 2019), and also mentioned the p.Lys311Glu variant, described in three patients by Dewald (2018). doi: 10.3389/fgene.2020.00304 I would like to clarify that Lys330Glu and Lys311Glu are actually two different names for the same Frontiers in Genetics | www.frontiersin.org 1 April 2020 | Volume 11 | Article 304 Colobran Plasminogen Mutation in Hereditary Angioedema FIGURE 1 | Plasminogen gene structure and location of the c.988A>G/p.Lys330Glu mutation at the DNA and protein level. The plasminogen gene (PLG) has 19 exons and is located on the long arm of chromosome 6 (6q26). The HAE-associated c.988A>G/p.Lys330Glu mutation is located in exon 9 and is included in the dbSNP database (ID rs889957249). The diagram of the plasminogen protein shows its different domains and numbering of the amino acids (based on UniProtKB: P00747). The p.Lys330Glu mutation is located in the kringle 3 domain. The alternative nomenclature, p.Lys311Glu, is based on the mature protein, and it excludes the first 19 amino acids of the signal peptide (SP). The chromosome 6 image was obtained from the Human Genome Project Archive. genetic variant. Lys330Glu refers to amino acid residue 330 also named c.988A>G/p.Lys330Glu (Dewald, 2018). However, of the primary translated protein, and Lys311Glu to amino this brief comment may go unnoticed by readers, and this acid residue 311 of the mature protein. The main reason for may have occurred in the case of Marcelino-Rodriguez et al. this discrepancy is the 19-amino-acid signal peptide present (2019). in the PLG protein, which allows it to be secreted to the Another confusing factor in reporting the PLG defect in extracellular region (Figure 1). The HGVS (Human Genome HAE is that in the original article by Bork at al. describing Variation Society) recommendations for describing sequence the p.Lys330Glu mutation, the name of the mutation at the variants state the following: “A protein reference sequence should cDNA level was incorrect in the abstract and results section. represent the primary translation product, not a processed mature Instead of c.988A>G, it appeared as c.9886A>G several times in protein, and thus includes the starting methionine, any signal the text (likely an involuntary typographic error). The authors peptide sequences, etc.” (den Dunnen et al., 2016). Therefore, noted the error and published a corrigendum several months the correct name for this PLG mutation at the protein level later (Bork et al., 2018a). is p.Lys330Glu. The aim of this commentary is simply to clarify that, At the cDNA level, different nomenclature was used by to date, only one PLG mutation causing HAE-PLG has Bork et al. in the article that first identified this mutation been discovered (c.988A>G/p.Lys330Glu), although the (c.988A>G) and by Georg Dewald (c.1100A>G) (Bork et al., aforementioned nomenclature-related factors may give a 2018b; Dewald, 2018). Nucleotide positions 988 and 1100 refer to different impression. Haplotype analysis demonstrated a founder the same position in the sequence of the canonical plasminogen effect that likely explains recurrence of this mutation in more transcript (NBCI reference sequence NM_000301.3): 988 is than 20 independent families identified so far (Bork et al., the position relative to the start codon, whereas 1100 is the 2018b). The existence of symptom-free carriers indicates that position relative to the transcription start site, containing 112 clinical penetrance is incomplete. Although the pathomechanism untranslated nucleotides before the first methionine. Again, of HAE-PLG has not been elucidated as yet, there is evidence the HGVS recommendations state: “cDNA numbering starts pointing to bradykinin as the main mediator of edema in this with ‘c.1’ at the A of the ATG translation initiation (start) condition; that is, bradykinin-2 receptor antagonist has been codon”. Therefore, the correct name for the PLG mutation effective in shortening acute attacks in several patients (Belbézier at the cDNA level is c.988A>G. Although Georg Dewald et al., 2018; Bork et al., 2018b; Recke et al., 2019). Whether or repeatedly uses the alternative nomenclature to describe the not other variants in PLG are a cause of HAE remains to be PLG mutation in his report (c.1100A>G/p.Lys311Glu), it must determined. In any case, in the current era of NGS capability, be said that at one point he indicates that this variant can be systematic use of the HGVS nomenclature is essential when Frontiers in Genetics | www.frontiersin.org 2 April 2020 | Volume 11 | Article 304 Colobran Plasminogen Mutation in Hereditary Angioedema reporting genetic variants to avoid misunderstandings on AUTHOR CONTRIBUTIONS dissemination of the information. Finally, another inaccuracy regarding the article by Marcelino- The author confirms being the sole contributor of this work and Rodriguez et al. can be pointed out. In Table 1, they selected has approved it for publication. 12 articles described as “genetic studies of acquired bradykinin- mediated angioedema.” However, the first manuscript from this FUNDING list is, as its title claims (Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families), a study of The author’s research was funded by Instituto de Salud Carlos HAE patients with normal C1-INH and mutations in F12 gene III, grant PI17/00660, cofinanced by the European Regional (Veronez et al., 2018), and not a study of acquired angioedema. Development Fund (ERDF). REFERENCES Germenis, A. E., Loules, G., Zamanakou, M., Psarros, F., González-Quevedo, T., Speletas, M., et al. (2018). On the pathogenicity of the plasminogen Bafunno, V., Firinu, D., D’Apolito, M., Cordisco, G., Loffredo, S., Leccese, A., K330E mutation for hereditary angioedema. Allergy 73, 1751–1753. et al. (2018). 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Missense mutations in the coagulation or reproduction in other forums is permitted, provided the original author(s) and factor XII (Hageman factor) gene in hereditary angioedema with the copyright owner(s) are credited and that the original publication in this journal normal C1 inhibitor. Biochem. Biophys. Res. Commun. 343, 1286–1289. is cited, in accordance with accepted academic practice. No use, distribution or doi: 10.1016/j.bbrc.2006.03.092 reproduction is permitted which does not comply with these terms. Frontiers in Genetics | www.frontiersin.org 3 April 2020 | Volume 11 | Article 304