1. bookVolume 27 (2019): Issue 3 (July 2019)
Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
access type Open Access

Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency

Published Online: 30 Jul 2019
Page range: 255 - 267
Received: 13 Feb 2019
Accepted: 31 May 2019
Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
Abstract

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity.

Keywords

1. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012;379(9814):474-81 DOI: 10.1016/S0140-6736(11)60935-510.1016/S0140-6736(11)60935-5Open DOISearch in Google Scholar

2. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-74 DOI: 10.1016/j.amjmed.2005.09.06410.1016/j.amjmed.2005.09.06416490473Open DOISearch in Google Scholar

3. Rosen FS, Davis AE III. Deficiencies of C1 inhibitor. Best Pract Res ClinGastroenterol. 2005;19:251-61 DOI: 10.1016/j.bpg.2004.11.01110.1016/j.bpg.2004.11.01115833691Open DOISearch in Google Scholar

4. Csép K, Moldovan D. Genetics of hereditary angioedema. Rev Romana Med Lab. 2010;18(1):7-13Search in Google Scholar

5. Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betscehl S, Bork K, et al. The international WAO/EAACI guideline for the management of hereditary angioedema - the 2017 revision and update. Allergy. 2018;73(8):1575-96 DOI: 10.1111/all.1338410.1111/all.1338429318628Search in Google Scholar

6. Germenis AE, Speletas M. Genetics of hereditary angioedema revisited. Clin Rev Allergy Immunol. 2016;51(2):170-82 DOI: 10.1007/s12016-016-8543-x10.1007/s12016-016-8543-x27116602Open DOISearch in Google Scholar

7. Speletas M, Szilagyi A, Psarros F, Moldovan D, Magerl M, Kompoti M, et al. Hereditary angioedema: molecular and clinical differences among European populations. J Allergy Clin Immunol. 2015;135(2):570-3 DOI: 10.1016/j.jaci.2014.08.00710.1016/j.jaci.2014.08.00725258140Open DOISearch in Google Scholar

8. Bygum A, Fagerberg CR, Ponard D, Monnier N, Lunardi J, Drouet C. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. Allergy. 2011;66:76-84 DOI: 10.1111/j.1398-9995.2010.02456.x10.1111/j.1398-9995.2010.02456.x20804470Search in Google Scholar

9. Rijavec M, Korošec P, Šilar M, Zidarn M, Miljković J, Košnik M. Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene. PLoS ONE. 2013;8(2):e56712 DOI: 10.1371/journal.pone.005671210.1371/journal.pone.0056712357775023437219Search in Google Scholar

10. Andrejević S, Korošec P, Šilar M, Košnik M, Mijanović R, Bonači-Nikolić B, et al. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association. PLoS ONE. 2015;10(11):e0142174 DOI: 10.1371/journal.pone.014217410.1371/journal.pone.0142174463303226535898Search in Google Scholar

11. Xu YY, Zhi YX, Yin J, Wang LL, Wen LP, Gu JQ, et al. Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema. Allergy. 2012;67(11):1430-6 DOI: 10.1111/all.1202410.1111/all.1202422994404Open DOISearch in Google Scholar

12. Sakshaug JW, West BT. Important considerations when analyzing health survey data collected using a complex sample design. Am J Public Health. 2014;104(1):15-6 DOI: 10.2105/AJPH.2013.30151510.2105/AJPH.2013.301515391004824228679Open DOISearch in Google Scholar

13. IBM. SPSS Complex Samples 22. Online: http://www.sussex.ac.uk/its/pdfs/SPSS_Complex_Samples_22.pdf Accessed: 11.01.2019Search in Google Scholar

14. Bouillet L, Launay D, Fain O, Boccon-Gibod I, Laurent J, Martin L, et al. Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patients. Ann Allergy Asthma Immunol. 2013;111(4):290-4 DOI: 10.1016/j.anai.2013.07.01210.1016/j.anai.2013.07.01224054366Open DOISearch in Google Scholar

15. Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009; 161:1153-1158 DOI: 10.1111/j.1365-2133.2009.09366.x10.1111/j.1365-2133.2009.09366.x19709101Open DOISearch in Google Scholar

16. Zanichelli A, Arcoleo F, Barca MP, Borrelli P, Bova M, Cancian M, et al. A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy. Orphanet J Rare Dis. 2015;10:11 DOI: 10.1186/s13023-015-0233-x10.1186/s13023-015-0233-x433389525758562Open DOISearch in Google Scholar

17. Speletas M, Szilagyi A, Csuka D, Koutsostathis N, Psarros F, Moldovan D, et al. F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema. Allergy. 2015;70(12):1661-4 DOI: 10.1111/all.1271410.1111/all.1271426248961Open DOISearch in Google Scholar

18. Cicardi M, Zingale LC, Zanichelli A, Pappalardo E, Cicardi B. C1 inhibitor: molecular and clinical aspects. Springer Semin Immun. 2005;27:286-98 DOI: 10.1007/s00281-005-0001-410.1007/s00281-005-0001-416267649Open DOISearch in Google Scholar

19. Pappalardo E, Zingale LC, Cicardi M. C1 inhibitor gene expression in patients with hereditary angioedema: quantitative evaluation by means of real-time RTPCR. J Allergy Clin Immunol. 2004;114(3):638-44 DOI: 10.1016/j.jaci.2004.06.02110.1016/j.jaci.2004.06.02115356570Open DOISearch in Google Scholar

20. Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A, et al. Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema. J Allergy Clin Immunol. 2000;106(6):1147-54 DOI: 10.1067/mai.2000.11047110.1067/mai.2000.11047111112899Open DOISearch in Google Scholar

21. Loules G, Zamanakou M, Parsopoulou F, Vatsiou S, Psarros F, Csuka D, et al. Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency. Gene. 2018;667:76-82 DOI: 10.1016/j.gene.2018.05.02910.1016/j.gene.2018.05.02929753808Open DOISearch in Google Scholar

22. Pappalardo E, Caccia S, Suffritti C, Tordai A, Zingale LC, Cicardi M. Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: Functional and structural correlates. Hum Immunol 2008;45:3536-44 DOI: 10.1016/j.molimm.2008.05.00710.1016/j.molimm.2008.05.00718586324Open DOISearch in Google Scholar

23. Lopez-Lera A, Garrido S, Roche O, Lopez-Trascasa M. SERPING1 mutations in 59 families with hereditary angioedema. Mol Immunol 2011;49:18-27 DOI: 10.1016/j.molimm.2011.07.01010.1016/j.molimm.2011.07.010Open DOISearch in Google Scholar

24. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133(1):1-9 DOI: 10.1007/s00439-013-1358-410.1007/s00439-013-1358-4Open DOISearch in Google Scholar

25. Kalmár L, Hegedüs T, Farkas H, Nagy M, Tordai A. HAEdb: a novel interactive, locus-specific mutation database for the C1 inhibitor gene. Hum Mutat. 2005;25(1):1-5 DOI: 10.1002/humu.2011210.1002/humu.20112Open DOISearch in Google Scholar

26. Amrani N, Sachs MS, Jacobsen A. Early nonsense: mRNA decay solves a translational problem. Nat Rev Mol Cell Biol. 2006;7(6):415-25 DOI: 10.1038/nrm194210.1038/nrm1942Open DOISearch in Google Scholar

27. Carter PE, Duponchel C, Tosi M, Fothergill JE. Complete nucleotide sequence for the C1 inhibitor with an unusually high density of Alu elements. Eur J Biochem. 1991;197(2):301-8 DOI: 10.1111/j.1432-1033.1991.tb15911.x10.1111/j.1432-1033.1991.tb15911.xSearch in Google Scholar

28. Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1-3 DOI: 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-OOpen DOISearch in Google Scholar

29. Bafunno V, Bova M, Loffredo S, Divella C, Petraroli A, Marone G, et al. Mutational Spectrum of the C1 Inhibitor Gene in a Cohort of Italian Patients with Hereditary Angioedema: Description of Nine Novel Mutations. Annals of Human Genetics. 2014;78(2):73-82 DOI: 10.1111/ahg.1205210.1111/ahg.12052Open DOISearch in Google Scholar

30. Davies MJ, Lomas DA. The molecular aetiology of the serpinopathies. Int J Biochem Cell Biol. 2008;40:1273-86 DOI: 10.1016/j.biocel.2007.12.01710.1016/j.biocel.2007.12.017Open DOISearch in Google Scholar

31. Eldering E, Verpy E, Roem D, Meo T, Tosi M. COOH-terminal substitutions in the serpin C1 inhibitor that cause loop overinsertion and subsequent multimerization. J Biol Chem. 1995;270:2579-87 DOI: 10.1074/jbc.270.6.257910.1074/jbc.270.6.2579Open DOISearch in Google Scholar

32. Aulak KS, Eldering E, Hack CE, Lubbers YP, Harrison RA, Mast A, et al. A hinge region mutation in C1-inhibitor (Ala436→Thr) results in nonsubstrate-like behavior and in polymerization of the molecule. J Biol Chem. 1993;268:18088-9410.1016/S0021-9258(17)46815-3Search in Google Scholar

33. Duponchel C, Djenouhat K, Frémeaux-Bacchi V, Monnier N, Drouet C, Tosi M. Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH. Hum Mutat. 2006;27(3):295-6 DOI: 10.1002/humu.941410.1002/humu.9414Open DOISearch in Google Scholar

34. Carter PE, Duponchel C, Tosi M, Fothergill JE. Complete nucleotide sequence for the C1 inhibitor with an unusually high density of Alu elements. Eur J Biochem. 1991;197(2):301-8 DOI: 10.1111/j.1432-1033.1991. tb15911.xSearch in Google Scholar

35. Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1-3 DOI: 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-OOpen DOISearch in Google Scholar

36. Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE. Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site. Proc Natl Acad Sci U S A 1990;87(17):6786-90 DOI: 10.1073/pnas.87.17.678610.1073/pnas.87.17.6786Open DOISearch in Google Scholar

37. Kramer J, Rosen FS, Colten HR, Rajczy K, Strunk RC. Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema. J Clin Invest. 1993;91:1258-62 DOI: 10.1172/JCI11629010.1172/JCI116290Open DOISearch in Google Scholar

38. Ernst SC, Circolo A, Davis AE 3rd, Gheesling-Mullis K, Fliesler M, Strunk RC. Impaired production of both normal and mutant C1 inhibitor proteins in type I hereditary angioedema with a duplication in exon 8. J Immunol. 1996;157:405-10Search in Google Scholar

39. Panagiota G, Gedeon L, Maria Z, Maria K, Dorottya Cs, Fotis P, et al. The KLKB1-Ser143Asn polymorphism: a new genetic biomarker predicting the age of disease onset in patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE). Allergy Asthma Clin Immunol. 2017;13(2):29Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo