In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency

Loli-Ausejo, David; López‐Lera, Alberto; Drouet, Christian; Lluncor, Marina; Phillips-Anglés, Elsa; Pedrosa, María; Cabañas, Rosario; Caballero, Teresa

doi:10.1007/s12016-021-08834-9

Cited by 7 publications

(3 citation statements)

References 26 publications

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“…Two insertions and deletions (N272del and K273del) have been reported. 24 , 25 Among the 3 fs variants, 2 (N166Qfs*91 and E85Dfs*63) were novel, whereas K201Qfs*56 had been noted. 26 These fs variations likely result in premature termination of C1-INH protein synthesis.…”

Section: Resultsmentioning

confidence: 98%

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

Ren¹,

Zhao²,

Li³

et al. 2023

Journal of Allergy and Clinical Immunology

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Section: Resultsmentioning

confidence: 98%

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

Ren¹,

Zhao²,

Li³

et al. 2023

Journal of Allergy and Clinical Immunology

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“…The mutant C1-INH significantly prevented the secretion of wild-type C1-INH, with its degradation within the cytoplasm through an interaction with the mutant protein ( 91 ). Observations of protease-resistant mutant C1-INH species suggest circulating latent C1-INH species that could also represent stable and low energetic conformations ( Figure 3B , Supplementary Table S3 ) ( 20 , 92 ).…”

Section: Inheritance Of Variantsmentioning

confidence: 99%

SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE

Drouet

López‐Lera

Ghannam³

et al. 2022

Front. Allergy

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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.

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“…In those rare cases when the edema evolves in the upper airways, the disease may lead to a potentially life-threatening condition within hours, without the proper treatment. Since the first pathogenic SERPING1 mutation was described in 1987 ( 1 ), the presence of C1-INH-HAE was explained by more than 700 different mutations ( 2 – 4 ) in the gene encoding C1-INH ( SERPING1 ) that can either cause decreased protein synthesis (C1-INH-HAE type I) or functional deficiency (C1-INH-HAE type II). The mutations in the background of C1-INH-HAE type II are usually missense mutations affecting the reactive center loop of C1-INH encoded in exon 8.…”

Section: Introductionmentioning

confidence: 99%

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

et al. 2022

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BackgroundHereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare autosomal dominant disorder, characterized by recurrent, unpredictable edematous symptoms involving subcutaneous, and/or submucosal tissue. C1-INH-HAE may be caused by more than 700 different mutations in the gene encoding C1-INH (SERPING1) that may lead to decreased protein synthesis or to functional deficiency.MethodsConcentrations of C1-INH, C4, C1q, and anti-C1-INH antibodies, as well as functional C1-INH activity were determined in subjects suffering from edematous symptoms and admitted to the Hungarian Angioedema Center of Reference and Excellence. In those patients, who were diagnosed with C1-INH-HAE based on the complement measurements, SERPING1 was screened by bidirectional sequencing following PCR amplification and multiplex ligation-dependent probe amplification. For detecting large deletions, long-range PCRs covering the entire SERPING1 gene by targeting 2–7 kb long regions were applied.ResultsAltogether 197 individuals with C1-INH deficiency belonging to 68 families were identified. By applying Sanger sequencing or copy number determination of SERPING1 exons, 48 different mutations were detected in 66/68 families: 5 large and 15 small insertions/deletions/delins, 16 missense, 6 nonsense, and 6 intronic splice site mutations. Two novel variations (p.Tyr199Ser [c.596A>C] and the duplication of exon 7) were shown to cosegregate with deficient C1-inhibitor level and activity, while two other variations were detected in single patients (c.797_800delinsCTTGGAGCTCAAGAACTTGGAGCT and c.812dup). A series of long PCRs was applied in the remaining 2 families without an identified mutation and a new, 2606 bp long deletion including the last 91 bp of exon 6 (c.939_1029+2515del) was identified in all affected members of one pedigree. In the remaining one family, a deep intronic SERPING1 variation (c.1029+384A>G) was detected by a targeted next-generation sequencing panel as reported previously.ConclusionsSequencing and copy number determination of SERPING1 exons uncover most pathogenic variants in C1-INH-HAE patients, and further methods are worth to be applied in cases with unrevealed genetic background. Since knowledge of the genetic background may support the establishment of the correct and early diagnosis of C1-INH-HAE, identification of causative mutations and reporting data supporting the interpretation on the pathogenicity of these variants is of utmost importance.

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In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency

Cited by 7 publications

References 26 publications

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses

SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema

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