ǂa ǂclose relationship with C1-INH-HAE

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

SERPING1 gene;C1-INH;C1-INH-HAE;C1 inhibitor;serpinopathy;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.02 - Pregledni znanstveni članek
Založnik: Frontiers
UDK: 575
COBISS: 103075331 Povezava se bo odprla v novem oknu
ISSN: 2673-6101
Št. ogledov: 194
Št. prenosov: 148
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarne ključne besede: gen SERPING1;C1-INH;C1-INH-HAE;zaviralec C1;serpinopatija;Angioedemas, hereditary;Genetics;Diagnosis;Genetic variation;Serpins;Hereditarni angioedemi;Genetika;Diagnostika;Genetska raznolikost;Serpini;
Komentar vira: Soavtor iz Slovenije: Matija Rijavec; Nasl. z nasl. zaslona; Opis vira z dne 1. 4. 2022;
Strani: str. 1-17
Zvezek: ǂVol. ǂ3
Čas izdaje: 31 Mar. 2022
DOI: 10.3389/falgy.2022.835503
ID: 14957355
Priporočena dela:
, ǂa ǂclose relationship with C1-INH-HAE
, clinical characteristics, novel SERPING1 mutations, and genetic factors modifying the clinical phenotype
, first national study, diagnostic and prophylactic challenges