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Naslov:SERPING1 variants and C1-INH biological function : a close relationship with C1-INH-HAE
Avtorji:Drouet, Christian (Avtor)
López Lera, Alberto (Avtor)
Ghannam, Arije (Avtor)
López-Trascasa, Margarita (Avtor)
Cichon, Sven (Avtor)
Ponard, Denise (Avtor)
Parsopoulou, Faidra (Avtor)
Grombirikova, Hana (Avtor)
Freiberger, Tomas (Avtor)
Rijavec, Matija (Avtor)
Lopes Veronez, Camila (Avtor)
Pesquero, João Bosco (Avtor)
Germenis, Anastasios E. (Avtor)
Jezik:Angleški jezik
Tipologija:1.02 - Pregledni znanstveni članek
Organizacija:Logo UKPBAG - Univerzitetna klinika za pljučne bolezni in alergijo Golnik
Povzetek: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.
Ključne besede:Hereditary angioedemas -- genetics -- diagnosis, genetic variation, serpins, SERPING1 gene, C1-INH, C1-INH-HAE, C1 inhibitor, serpinopathy
Leto izida:2022
Založnik:Frontiers
Izvor:Švica
UDK:575
ISSN pri članku:2673-6101
COBISS_ID:103075331 Povezava se odpre v novem oknu
DOI:10.3389/falgy.2022.835503 Povezava se odpre v novem oknu
Opombe:Soavtor iz Slovenije: Matija Rijavec; Nasl. z nasl. zaslona; Opis vira z dne 1. 4. 2022;
Število ogledov:141
Število prenosov:100
Datoteke:.pdf PDF - Predstavitvena datoteka, prenos (2,51 MB)
.docx DOCX - Predstavitvena datoteka, prenos (26,80 KB)
 
Nadgradivo:Front. allergy
Frontiers Media
 
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
Avtorske pravice:© 2022 Drouet, López-Lera, Ghannam, López-Trascasa, Cichon, Ponard, Parsopoulou, Grombirikova, Freiberger, Rijavec, Veronez, Pesquero and Germenis
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Licenca:CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
Povezava:http://creativecommons.org/licenses/by/4.0/deed.sl
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Začetek licenciranja:31.03.2022

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