SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE
Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the...
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Allergy |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/falgy.2022.835503/full |
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| author | Christian Drouet Christian Drouet Alberto López-Lera Arije Ghannam Margarita López-Trascasa Sven Cichon Sven Cichon Denise Ponard Faidra Parsopoulou Hana Grombirikova Tomáš Freiberger Matija Rijavec Camila L. Veronez João Bosco Pesquero Anastasios E. Germenis Anastasios E. Germenis |
| author_facet | Christian Drouet Christian Drouet Alberto López-Lera Arije Ghannam Margarita López-Trascasa Sven Cichon Sven Cichon Denise Ponard Faidra Parsopoulou Hana Grombirikova Tomáš Freiberger Matija Rijavec Camila L. Veronez João Bosco Pesquero Anastasios E. Germenis Anastasios E. Germenis |
| author_sort | Christian Drouet |
| collection | DOAJ |
| description | Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy. |
| first_indexed | 2024-12-14T05:46:57Z |
| format | Article |
| id | doaj.art-e85a9382b14b477ba2a0dacd75879689 |
| institution | Directory Open Access Journal |
| issn | 2673-6101 |
| language | English |
| last_indexed | 2024-12-14T05:46:57Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Allergy |
| spelling | doaj.art-e85a9382b14b477ba2a0dacd758796892022-12-21T23:14:50ZengFrontiers Media S.A.Frontiers in Allergy2673-61012022-03-01310.3389/falgy.2022.835503835503SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAEChristian Drouet0Christian Drouet1Alberto López-Lera2Arije Ghannam3Margarita López-Trascasa4Sven Cichon5Sven Cichon6Denise Ponard7Faidra Parsopoulou8Hana Grombirikova9Tomáš Freiberger10Matija Rijavec11Camila L. Veronez12João Bosco Pesquero13Anastasios E. Germenis14Anastasios E. Germenis15Department of Infection, Immunity and Inflammation, Institut Cochin, INSERM UMR1016, Université de Paris, Paris, FranceUniv. Grenoble-Alpes & Centre Hospitalier Universitaire de Grenoble, Grenoble, FranceHospital La Paz Institute for Health Research (IdiPAZ), CIBERER U-754, Madrid, SpainKininX SAS, Grenoble, FranceHospital La Paz Institute for Health Research (IdiPAZ), Universidad Autónoma de Madrid, Madrid, SpainHuman Genomics Research Group, Department of Biomedicine, University of Basel, Basel, SwitzerlandInstitute of Medical Genetics and Pathology, University Hospital Basel, Basel, SwitzerlandCentre Hospitalier Universitaire de Grenoble, Grenoble, FranceCeMIA SA, Larissa, Greece0Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty, Masaryk University, Brno, Czechia0Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty, Masaryk University, Brno, Czechia1University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia2Department of Biophysics, Centre for Research and Genetic Diagnosis of Genetic Diseases, Federal University of São Paolo, São Paolo, Brazil2Department of Biophysics, Centre for Research and Genetic Diagnosis of Genetic Diseases, Federal University of São Paolo, São Paolo, BrazilCeMIA SA, Larissa, Greece3Department of Immunology & Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa, GreeceHereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.https://www.frontiersin.org/articles/10.3389/falgy.2022.835503/fullC1-INH-HAEC1 InhibitorSERPING1 genegenetic variationserpin functionserpinopathy |
| spellingShingle | Christian Drouet Christian Drouet Alberto López-Lera Arije Ghannam Margarita López-Trascasa Sven Cichon Sven Cichon Denise Ponard Faidra Parsopoulou Hana Grombirikova Tomáš Freiberger Matija Rijavec Camila L. Veronez João Bosco Pesquero Anastasios E. Germenis Anastasios E. Germenis SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE Frontiers in Allergy C1-INH-HAE C1 Inhibitor SERPING1 gene genetic variation serpin function serpinopathy |
| title | SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE |
| title_full | SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE |
| title_fullStr | SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE |
| title_full_unstemmed | SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE |
| title_short | SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE |
| title_sort | serping1 variants and c1 inh biological function a close relationship with c1 inh hae |
| topic | C1-INH-HAE C1 Inhibitor SERPING1 gene genetic variation serpin function serpinopathy |
| url | https://www.frontiersin.org/articles/10.3389/falgy.2022.835503/full |
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