Deletions in <b><i>SERPING1</i></b> Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity

Abstract

Background: How genotype affects phenotype in hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) has not been totally clarified. In this study, we investigated the relationship between different types of mutations and various phenotypic characteristics. Methods: Clinical data from 81 patients from 47 families were recorded. Complement proteins were analyzed from 61 untreated patients. The coding exons and the exon-intron boundaries of the SERPING1 gene were sequenced, and deletion/duplication analysis with multiple ligation dependent probe amplification was performed. The relationship of complement protein with the mutation type was analyzed by using generalized estimating equations. Results: Thirty-five different mutations (15 novel and 2/15 homozygous) were identified. There was no causative mutation in 6 patients (7.4%). Patients with deletion and large deletion had the lowest (5.05%, 0–18.7; 5.8%, 0–16.5%, respectively), and the none mutation group had the highest C1 inhibitor function (23.3%, 11–78%, p < 0.001). C1 inhibitor function levels decreased as the age of the disease progressed (r = –0.352, p = 0.005). Lower C1 inhibitor function levels caused severer disease (r = –0.404, p = 0.001) and more frequent annual attacks (r = –0.289, p = 0.024). In the off-attack period, C1q levels were lower than normal in 9.8% of the patients. Conclusion: Deletion mutations may represent the most unfavorable effect on C1 inhibitor function. The earlier disease onset age could be a sign for lower C1 inhibitor function levels in adult life. C1q levels could also be low in C1-INH-HAE patients, as in acquired angioedema. Lower C1 inhibitor function can predict disease severity and may have negative impacts on the course of C1-INH-HAE.

<p>Idiopathic Angioedema: Current Challenges</p>

“…33,34 Low levels of C1q are highly specific to C1-inh-AAE and seen in 7°% of cases. However, some genetically proven C1-inh-HAE can also show low C1q levels s. 35,36 Anti-C1-inh antibodies are present in 60% of cases. 37 Hemopathies and AAE seem to be linked, with, 40% of C1-inh-AAE associated with a monoclonal gammopathy of undetermined significance, in which monoclonal and anti-C1-inh antibodies share the same isotype.…”

Effects of nutraceutical intervention on serum proteins in aged rats

“…Serpin G1, also called C1 inhibitor or C1 esterase inhibitor, is largely considered to be a protective factor, and its inhibition has been associated with impaired blood-brain barrier (BBB) integrity and neuroinflammation in the brain (Farfara et al 2019). Furthermore, deficient C1 inhibitor expression is linked to hereditary angioedema (Mete Gokmen et al 2019), further suggesting a protective function.…”

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

“…Low C1q levels were found in 70–80% of AAE-C1-INH patients, while they were normal in those with HAE-C1-INH [3-6]. However, on rare occasions, an absence of C1q has been reported in homozygous HAE-C1-INH patients [12, 13], and low levels of C1q have been found in ∼10% of heterozygous as well as homozygous HAE-C1-INH patients from Turkey in attack-free periods [14]. The presence of anti-C1-INH autoantibodies and the absence of mutations in SERPING1 may indicate the diagnosis of AAE-C1-INH [4, 8]; however, testing for anti-C1-INH antibodies, which are present in ∼70% of the patients, is not readily available outside reference laboratories, and mutations in the gene coding for C1-INH have not been encountered in 5% of patients with HAE-C1-INH [4, 15].…”