SERPING1 variants and C1-INH biological function

ǂa ǂclose relationship with C1-INH-HAE

Christian Drouet (Avtor), Alberto López Lera (Avtor), Arije Ghannam (Avtor), Margarita López-Trascasa (Avtor), Sven Cichon (Avtor), Denise Ponard (Avtor), Anastasios E. Germenis (Avtor), Faidra Parsopoulou (Avtor), Hana Grombirikova (Avtor), Tomas Freiberger (Avtor), Matija Rijavec (Avtor), Camila Lopes Veronez (Avtor), João Bosco Pesquero (Avtor)

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:	2022
Tipologija:	1.02 - Pregledni znanstveni članek
Založnik:	Frontiers
UDK:	575
COBISS:	103075331
ISSN:	2673-6101
Št. ogledov:	194
Št. prenosov:	148
Ocena:	0 (0 glasov)
Metapodatki:

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