C1-inhibitor (C1-INH) is a serpin controlling complement and kinin/contact system activation. Mutations in the C1-INH gene (SERPING1) almost consistently result in reduced C1-INH functional level in plasma causing hereditary angioedema (HAE), a life-threatening autosomal dominant disorder (estimated prevalence of 1:50,000). Despite the stable defect in C1-INH plasma levels, triggering mechanisms and clinical expressions of HAE are still unpredictable. Moreover, molecular processes underlying the disease as well as genotype-phenotype correlations remain largely undisclosed, although more than 200 HAE-causing mutations in SERPING1 have been described to date. Interestingly, plasma levels of functional C1-INH in most HAE patients are markedly below the half normal levels that the wild-type allele should provide, suggesting a down regulation of SERPING1 wild-type allele. This hypothesis was initially strengthened by previous studies demonstrating that total SERPING1 mRNA levels were below 50% in HAE patients, independently of the type of mutation (missense, nonsense, frameshift, …). In this frame, we analyzed total SERPING1 mRNA level in whole blood in a cohort of 10 HAE patients carrying different mutations and in an equal number of controls. Our data do not confirm previous findings on SERPING1 mRNA levels. Generally, no differences in SERPING1 mRNA expression levels were found between controls and HAE patients carrying missense mutations. Allele-specific SERPING1 mRNA dosage demonstrated that nonsense mutations followed the classical Nonsense-Mediated mRNA Decay (NMD) rule. Notably, all nucleotide changes mapping in proximity of position 16872 in the last SERPING1 exon and leading either to nonsense or missense mutations unexpectedly were associated with a considerable mRNA degradation. These findings were surprising in light of the fact that these nonsense mutations reside within the terminal exon and thus would not be expected to trigger NMD. The observation that also a missense mutation in the same region is associated with the allele-specific reduction of SERPING1 mRNA, confirms that mRNA decay is independent from NMD and suggests that it might be due to the disturbance of a putative mRNA stability element in this region. A better understanding of C1−INH gene regulation and of its role in HAE pathogenesis could be critical to provide targets for new therapeutic approaches to cure this neglected, severe genetic disease.

Gene regulation in the pathogenesis of inherited C1-inhibitor deficiency (Hereditary Angioedema) / S. Caccia, V. Rimoldi, R. Asselta, G.M. Soldà, E. Bonanni, R. Russo, S. Duga, M. Cicardi. ((Intervento presentato al 6. convegno International Symposium on the Chemistry and Biology of serpins tenutosi a Chapel nel 2011.

Gene regulation in the pathogenesis of inherited C1-inhibitor deficiency (Hereditary Angioedema)

S. Caccia
Primo
;
V. Rimoldi
Secondo
;
R. Asselta;G.M. Soldà;R. Russo;S. Duga
Penultimo
;
M. Cicardi
Ultimo
2011

Abstract

C1-inhibitor (C1-INH) is a serpin controlling complement and kinin/contact system activation. Mutations in the C1-INH gene (SERPING1) almost consistently result in reduced C1-INH functional level in plasma causing hereditary angioedema (HAE), a life-threatening autosomal dominant disorder (estimated prevalence of 1:50,000). Despite the stable defect in C1-INH plasma levels, triggering mechanisms and clinical expressions of HAE are still unpredictable. Moreover, molecular processes underlying the disease as well as genotype-phenotype correlations remain largely undisclosed, although more than 200 HAE-causing mutations in SERPING1 have been described to date. Interestingly, plasma levels of functional C1-INH in most HAE patients are markedly below the half normal levels that the wild-type allele should provide, suggesting a down regulation of SERPING1 wild-type allele. This hypothesis was initially strengthened by previous studies demonstrating that total SERPING1 mRNA levels were below 50% in HAE patients, independently of the type of mutation (missense, nonsense, frameshift, …). In this frame, we analyzed total SERPING1 mRNA level in whole blood in a cohort of 10 HAE patients carrying different mutations and in an equal number of controls. Our data do not confirm previous findings on SERPING1 mRNA levels. Generally, no differences in SERPING1 mRNA expression levels were found between controls and HAE patients carrying missense mutations. Allele-specific SERPING1 mRNA dosage demonstrated that nonsense mutations followed the classical Nonsense-Mediated mRNA Decay (NMD) rule. Notably, all nucleotide changes mapping in proximity of position 16872 in the last SERPING1 exon and leading either to nonsense or missense mutations unexpectedly were associated with a considerable mRNA degradation. These findings were surprising in light of the fact that these nonsense mutations reside within the terminal exon and thus would not be expected to trigger NMD. The observation that also a missense mutation in the same region is associated with the allele-specific reduction of SERPING1 mRNA, confirms that mRNA decay is independent from NMD and suggests that it might be due to the disturbance of a putative mRNA stability element in this region. A better understanding of C1−INH gene regulation and of its role in HAE pathogenesis could be critical to provide targets for new therapeutic approaches to cure this neglected, severe genetic disease.
Settore BIO/11 - Biologia Molecolare
Settore MED/09 - Medicina Interna
University North Carolina School of Medicine
University Pittsburgh Medical Center Children's Hospital
University of Cambridge
Gene regulation in the pathogenesis of inherited C1-inhibitor deficiency (Hereditary Angioedema) / S. Caccia, V. Rimoldi, R. Asselta, G.M. Soldà, E. Bonanni, R. Russo, S. Duga, M. Cicardi. ((Intervento presentato al 6. convegno International Symposium on the Chemistry and Biology of serpins tenutosi a Chapel nel 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/164927
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