Identification and characterization of a novel splice site mutation in the SERPING1 gene in a family with hereditary angioedema

Colobran, Roger; Lois, Sergio; Cruz, Xavier de la; Pujol-Borrell, Ricardo; Hernández‐González, Manuel; Guilarte, Mar

doi:10.1016/j.clim.2013.11.013

Cited by 9 publications

(3 citation statements)

References 24 publications

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“…In Danish patients expressing this exon 4-deleted mRNA, the disease allele contains a larger genomic deletion spanning exon 4 and including parts of the flanking introns. Notably however, splice site mutations in this region (typically in the splice acceptor site in the intron upstream of exon 4) can lead to formation of the exact same mutated protein, and HAE type I patients with this particular type of mutation have been described in previous reports (4,40). Differences in the potential to form C1INH aggregates among the different HAE-causing C1INH variants and the particular severity of C1INH Gly162_Pro206del may reflect how the mutation affects the structure of the C1INH protein.…”

Section: Discussionmentioning

confidence: 98%

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

Haslund¹,

Ryø²,

Majidi³

et al. 2018

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 98%

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

Haslund¹,

Ryø²,

Majidi³

et al. 2018

Journal of Clinical Investigation

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“…The most recently known RNA surveillance mechanism is No‐Go Decay (NGD), in which aberrant secondary structures causing stalls in translation elongation trigger mRNA endonucleolytic cleavage . NGD has been described as the pathogenic mechanism in other splice site mutation, causing human disease …”

Section: Discussionmentioning

confidence: 99%

NOVEL intronic CAPN3 Roma mutation alters splicing causing RNA mediated decay

Mavillard

Madruga‐Garrido

Rivas

et al. 2019

Ann Clin Transl Neurol

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CAPN3 mutations cause a limb girdle muscular dystrophy. Functional characterization of novel mutations facilitates diagnosis of future cases. We have identified a novel (c.1992 + 2T>G) CAPN3 mutation that disrupts the donor splice site of intron 17 splicing out exon 17, with mRNA levels severely reduced or undetectable. The mutation induces a strong change in the 3D structure of the mRNA which supports no‐go mRNA decay as the probable mechanism for RNA degradation. The mutation was identified in two unrelated Roma individuals showing a common ancestral origin and founder effect. This is the first Roma CAPN3 mutation to be reported.

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“…Interestingly, Colobran et al detected c.6852 + T>A in intron 4. Functional studies of the mRNA demonstrated that this variant leads to the omission of exon 4 ( 73 ). Exon 4 consists of 135 bp (i.e., 45 codons); the lack of exon 4 corresponds to an in-frame deletion.…”

Section: Distribution 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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Identification and characterization of a novel splice site mutation in the SERPING1 gene in a family with hereditary angioedema

Cited by 9 publications

References 24 publications

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

NOVEL intronic CAPN3 Roma mutation alters splicing causing RNA mediated decay

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

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