20.500.12556/DiRROS-14959 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 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. Hereditary angioedemas -- genetics -- diagnosis genetic variation serpins SERPING1 gene C1-INH C1-INH-HAE C1 inhibitor serpinopathy hereditarni angioedemi -- genetika -- diagnostika genetska raznolikost serpini gen SERPING1 C1-INH C1-INH-HAE zaviralec C1 serpinopatija true false true Frontiers Angleški jezik Ni določen © 2022 Drouet, López-Lera, Ghannam, López-Trascasa, Cichon, Ponard, Parsopoulou, Grombirikova, Freiberger, Rijavec, Veronez, Pesquero and Germenis Neznano 2022-04-06 11:49:19 2022-04-06 11:49:22 2022-08-21 03:34:20 0000-00-00 00:00:00 2022 0 Švica 0 Soavtor iz Slovenije: Matija Rijavec; Nasl. z nasl. zaslona; Opis vira z dne 1. 4. 2022; str. 1-17 Vol. 3 31 Mar. 2022 0000-00-00 Zaloznikova VTisku NiDoloceno 0000-00-00 0000-00-00 0000-00-00 575 2673-6101 10.3389/falgy.2022.835503 103075331 RAZ_Drouet_Christian_i2022.pdf RAZ_Drouet_Christian_i2022.pdf 1 1EC42A4C79F75680BD123AD1204A8624 d1c8a93fdce83138c79f06233d7d25d8bfea63749d0c1381b990a71ebaab5675 e1be2236-17b6-11ed-b6b8-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=19420 RAZ_Drouet_Christian_i2022.DOCX RAZ_Drouet_Christian_i2022.DOCX 1 AD9A98F30A12155544BD5EA76EF83F5B 4324220c5c54b1dd063c44002010647b78c236e669eb1873aad3e689d2cec804 e1d139fd-17b6-11ed-b6b8-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=19421 Univerzitetna klinika za pljučne bolezni in alergijo Golnik 0 0 0