Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema - Université Grenoble Alpes Accéder directement au contenu
Article Dans Une Revue (Data Paper) Journal of Clinical Medicine Année : 2023

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

Résumé

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.
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Dates et versions

hal-04464362 , version 1 (11-04-2024)

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Luana Sella Motta Maia, Bettina Burger, Arije Ghannam, Fernanda Leonel Nunes, Mariana Paes Leme Ferriani, et al.. Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema. Journal of Clinical Medicine, 2023, Updates in Kallikrein-Kinin System, 12, pp.7299. ⟨10.3390/jcm12237299⟩. ⟨hal-04464362⟩

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