No Evidence for Linkage between the Hereditary Angiooedema Clinical Phenotype and the BDKR1, BDKR2, ACE or MBL2 gene

Freiberger, Tomáš; Grombiříková, Hana; Ravčuková, Barbora; Jarkovský, Jiří; Kuklı́nek, Pavel; Kryštůfková, Olga; Hanzlı́ková, Jana; Daňková, Eva; Kopecký, O; Zachová, Radana; Lahodná, Marie; Vašáková, Martina; Grodecká, Lucie; Litzman, Jiří

doi:10.1111/j.1365-3083.2011.02547.x

Cited by 17 publications

(19 citation statements)

References 27 publications

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“…In addition, the first attacks occurred later in the FXII‐HAE group than the C1Inh‐HAE, with symptoms developing after aged 12 in 82.5% of FXII‐HAE patients (Table. S1) and 62% of those with C1Inh‐HAE . Consequently, these considerations required the severity scaling of Freiberger et al.…”

Section: Discussionmentioning

confidence: 99%

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Hereditary angioedema withF12mutation: factors modifying the clinical phenotype

Charignon

Ghannam

Defendi

et al. 2014

Allergy

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Section: Discussionmentioning

confidence: 99%

“… and Freiberger et al. . Classification was determined following adaptation to the specificity of nC1Inh‐HAE clinical phenotype (attack frequency and age at symptom onset).…”

Section: Methodsmentioning

confidence: 99%

Hereditary angioedema withF12mutation: factors modifying the clinical phenotype

Charignon

Ghannam

Defendi

et al. 2014

Allergy

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“…In addition, we showed that C1 inhibitor function levels strongly correlated with disease severity determined by a well-defined symptom severity score (Fig. 1) [13]. C1 inhibitor function has also been reported to be positively correlated with another disease severity index [24].…”

Section: Discussionmentioning

confidence: 95%

“…None of the patients were on angiotensin-converting enzyme inhibitor treatment or estrogen-based therapy. The symptom severity was assessed by a well-defined scoring system in the pretreatment period [13]. This study was approved by the Ethics Committee of Ege University (B.30.2.EGE.0.20.05.00/OY/1128/ 456) and was conducted according to the principles of good clinical practice and adhered strictly to the ethical standards outlined in the Declaration of Helsinki [14].…”

Section: Methodsmentioning

confidence: 99%

Deletions in SERPING1 Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity

Gökmen

Gülbahar

Önay

et al. 2018

Int Arch Allergy Immunol

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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.

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“…The results presented shed more light on the interface between innate and adaptive immunity in the context of C1-INH deficiency and question the role of local C1-INH synthesis by PBMCs in HAE patients. Effectively, not the PBMCs synthesis of C1-INH mRNA, nor that of other molecules classically implicated in the pathogenesis of HAE like Angiotensin Converting Enzyme (ACE), Bradykinin Receptors 1 and 2, (BDKR1, BDKR2) or Aminopeptidase P (APP) showed any statistical effect on the frequency of HAE attacks [18,19]. In agreement with that, instead of a common disease-associated signature, PBMCs from the three families analyzed exhibit different expression patterns linked to their symptoms.…”

Section: Discussionmentioning

confidence: 99%

Disease-modifying factors in hereditary angioedema: an RNA expression-based screening

López-Lera

Sánchez‐Cabo

Garrido

et al. 2013

Orphanet J Rare Dis

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BackgroundHereditary Angioedema due to C1-Inhibitor deficiency (HAE types I and II) is a monogenic disease characterized by sudden, self-limited episodes of cutaneous and mucosal swelling due to local deregulation of vascular permeability. Despite its monogenic pattern of inheritance, HAE exhibits great clinical variability and low genotype/phenotype correlation among those affected, which ultimately hinders therapeutic approach and probably underlies yet unknown genetic and environmental factors.MethodsWe studied whole-genome RNA expression of PBMCs in three HAE type-I families (accounting for 40 individuals), 24 of which carry the same R472X mutation in the C1-Inhibitor gene and show large variability in terms of disease expression. Those included in this study were analyzed according to the presence of mutation and/or clinical symptoms.ResultsInstead of a single, common disease-associated expression pattern, we found different transcriptome signatures in two of the families studied. In one of them (referred to as DR family), symptoms correlate with the upregulation of 35 genes associated to the biological response to viral infections (including RSADs, OAS, MX and ISG pathway members) and immune response. In another pedigree (Q family), disease manifestation is linked to the upregulation of 43 genes with diverse functions, including transcription and protein folding. Moreover, symptoms-free members of the Q pedigree display relatively higher expression of 394 genes with a wide diversity of functions.ConclusionWe found no evidence for a common altered PBMC expression pattern linked to HAE symptoms in the three families analyzed. All the data considered, differential gene expression in PBMCs do not seem to play a significant role in the predisposition or protection against HAE in the basal -between crises- conditions analyzed. Although the RNA expression pattern associated to the response to viral infections observed in the DR family supports the idea of infectious diseases as a modifying factor for HAE severity, large-scale studies would be needed to statistically associate such expression pattern to the development of this rare disease.

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No Evidence for Linkage between the Hereditary Angiooedema Clinical Phenotype and the BDKR1, BDKR2, ACE or MBL2 gene

Cited by 17 publications

References 27 publications

Hereditary angioedema withF12mutation: factors modifying the clinical phenotype

Hereditary angioedema withF12mutation: factors modifying the clinical phenotype

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

Disease-modifying factors in hereditary angioedema: an RNA expression-based screening

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