Recessive SERPING1 Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.
J Clin Med
; 12(23)2023 Nov 24.
Article
em En
| MEDLINE
| ID: mdl-38068351
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_000062.3c.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.
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
País/Região como assunto:
America do sul
/
Brasil
Idioma:
En
Revista:
J Clin Med
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Suíça