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Recessive SERPING1 Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.

ABSTRACT: Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant's effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.

SUBMITTER: Maia LSM

PROVIDER: S-EPMC10707408 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Recessive SERPING1 Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.

Maia Luana Sella Motta LSM Burger Bettina B Ghannam Arije A Nunes Fernanda Leonel FL Ferriani Mariana Paes Leme MPL Dias Marina Mendonça MM Arruda Luisa Karla LK Drouet Christian C Cichon Sven S

Journal of clinical medicine 20231124 23

Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in ...[more]

PMID: 38068351

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Project description:BackgroundHereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE.MethodsPharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial.ResultsKVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106 M-1 s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage.ConclusionKVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.

Project description:Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease.

Dataset Information

Recessive SERPING1 Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.

Publications

Recessive <i>SERPING1</i> Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.

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