Skip to main content

Novel Mutations Causing C5 Deficiency in Three North-African Families

Journal of Clinical Immunology volume 36, pages 388–396 (2016)Cite this article

Abstract

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kolev M, Le Friec G, Kemper C. Complement--tapping into new sites and effector systems. Nat Rev Immunol. 2014;14(12):811–20.

    Article  CAS  PubMed  Google Scholar 

  3. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I—molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262.

    PubMed  PubMed Central  Google Scholar 

  4. Carney DF, Haviland DL, Noack D, Wetsel RA, Vik DP, Tack BF. Structural aspects of the human C5 gene. Intron/exon organization, 5′-flanking region features, and characterization of two truncated cdna clones. J Biol Chem. 1991;266(28):18786–91.

    CAS  PubMed  Google Scholar 

  5. Tack BF, Morris SC, Prahl JW. Fifth component of human complement: purification from plasma and polypeptide chain structure. Biochemistry. 1979;18(8):1490–7.

    Article  CAS  PubMed  Google Scholar 

  6. Guo RF, Ward PA. Role of c5a in inflammatory responses. Annu Rev Immunol. 2005;23:821–52.

    Article  CAS  PubMed  Google Scholar 

  7. Laursen NS, Magnani F, Gottfredsen RH, Petersen SV, Andersen GR. Structure, function and control of complement C5 and its proteolytic fragments. Curr Mol Med. 2012;12(8):1083–97.

    Article  CAS  PubMed  Google Scholar 

  8. Haviland DL, Haviland JC, Fleischer DT, Wetsel RA. Structure of the murine fifth complement component (C5) gene. A large, highly interrupted gene with a variant donor splice site and organizational homology with the third and fourth complement component genes. J Biol Chem. 1991;266(18):11818–25.

    CAS  PubMed  Google Scholar 

  9. Peter G, Weigert MB, Bissel AR, Gold R, Kreutzer D, McLean RH. Meningococcal meningitis in familial deficiency of the fifth component of complement. Pediatrics. 1981;67(6):882–6.

    CAS  PubMed  Google Scholar 

  10. Figueroa J, Andreoni J, Densen P. Complement deficiency states and meningococcal disease. Immunol Res. 1993;12(3):295–311.

    Article  CAS  PubMed  Google Scholar 

  11. Delgado-Cerviño E, Fontán G, López-Trascasa M. C5 complement deficiency in a spanish family. Molecular characterization of the double mutation responsible for the defect. Mol Immunol. 2005;42(1):105–11.

    Article  PubMed  Google Scholar 

  12. Aguilar-Ramirez P, Reis ES, Florido MP, Barbosa AS, Farah CS, Costa-Carvalho BT, et al. Skipping of exon 30 in C5 gene results in complete human C5 deficiency and demonstrates the importance of c5d and CUB domains for stability. Mol Immunol. 2009;46(10):2116–23.

    Article  CAS  PubMed  Google Scholar 

  13. Lappegård KT, Christiansen D, Pharo A, Thorgersen EB, Hellerud BC, Lindstad J, et al. Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature. Proc Natl Acad Sci U S A. 2009;106(37):15861–6.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Schejbel L, Fadnes D, Permin H, Lappegård KT, Garred P, Mollnes TE. Primary complement C5 deficiencies—molecular characterization and clinical review of two families. Immunobiology. 2013;218(10):1304–10.

    Article  CAS  PubMed  Google Scholar 

  15. Pfarr N, Prawitt D, Kirschfink M, Schroff C, Knuf M, Habermehl P, et al. Linking C5 deficiency to an exonic splicing enhancer mutation. J Immunol. 2005;174(7):4172–7.

    Article  CAS  PubMed  Google Scholar 

  16. López-Lera A, Garrido S, de la Cruz RM, Fontán G, López-Trascasa M. Molecular characterization of three new mutations causing C5 deficiency in two non-related families. Mol Immunol. 2009;46(11–12):2340–7.

    Article  PubMed  Google Scholar 

  17. Owen EP, Würzner R, Leisegang F, Rizkallah P, Whitelaw A, Simpson J, et al. A complement C5 gene mutation, c.754G > A:P.A252T, is common in the western cape, south africa and found to be homozygous in seven percent of black african meningococcal disease cases. Mol Immunol. 2015;64(1):170–6.

    Article  CAS  PubMed  Google Scholar 

  18. Arnaout R, Al Shorbaghi S, Al Dhekri H, Al-Mousa H, Al Ghonaium A, Al Saud B, et al. C5 complement deficiency in a saudi family, molecular characterization of mutation and literature review. J Clin Immunol. 2013;33(4):871–5.

    Article  CAS  PubMed  Google Scholar 

  19. Wang X, Fleischer DT, Whitehead WT, Haviland DL, Rosenfeld SI, Leddy JP, et al. Inherited human complement C5 deficiency. Nonsense mutations in exons 1 (gln1 to stop) and 36 (arg1458 to stop) and compound heterozygosity in three African-American families. J Immunol. 1995;154(10):5464–71.

    CAS  PubMed  Google Scholar 

  20. Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, et al. Comparative protein structure modeling using MODELLER. Curr Protoc Protein Sci. 2007;Chapter 2:Unit 2.9.

  21. Fredslund F, Laursen NS, Roversi P, Jenner L, Oliveira CL, Pedersen JS, et al. Structure of and influence of a tick complement inhibitor on human complement component 5. Nat Immunol. 2008;9(7):753–60.

    Article  CAS  PubMed  Google Scholar 

  22. Hellerud BC, Aase A, Herstad TK, Naess LM, Kristiansen LH, Trøseid AM, et al. Critical roles of complement and antibodies in host defense mechanisms against neisseria meningitidis as revealed by human complement genetic deficiencies. Infect Immun. 2010;78(2):802–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu X, Brewer G. The regulation of mRNA stability in mammalian cells: 2.0. Gene. 2012;500(1):10–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Henn BM, Botigué LR, Gravel S, Wang W, Brisbin A, Byrnes JK, et al. Genomic ancestry of north Africans supports back-to-Africa migrations. PLoS Genet. 2012;8(1), e1002397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fadhlaoui-Zid K, Haber M, Martínez-Cruz B, Zalloua P, Benammar Elgaaied A, Comas D. Genome-wide and paternal diversity reveal a recent origin of human populations in north africa. PLoS One. 2013;8(11), e80293.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65.

    Article  PubMed  Google Scholar 

  27. Cheng SC, Sprong T, Joosten LA, van der Meer JW, Kullberg BJ, Hube B, et al. Complement plays a central role in candida albicans-induced cytokine production by human pbmcs. Eur J Immunol. 2012;42(4):993–1004.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are deeply grateful to all the affected individuals and their families who participated in this study. This study was funded by Instituto de Salud Carlos III, grant PI14/00405, cofinanced by the European Regional Development Fund (ERDF), and by MINECO grant CGL2013-44351-P. We thank Karima Fadhlaoui-Zid for providing some North-African DNA samples.

Author information

Author notes

    Authors and Affiliations

    1. Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

      Roger Colobran, Clara Franco-Jarava, Ricardo Pujol-Borrell & Manuel Hernández-González

    2. Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Edifici Laboratoris, planta baixa. Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain

      Roger Colobran

    3. Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

      Andrea Martín-Nalda & Pere Soler-Palacín

    4. Genetic Laboratory UDIAT-Diagnostic Center, Corporació Sanitària Parc Taulí, Sabadell, Spain

      Neus Baena & Elisabeth Gabau

    5. Research Unit in Translational Bioinformatics, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

      Natàlia Padilla & Xavier de la Cruz

    6. Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain

      David Comas

    Authors
    1. Roger Colobran
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Clara Franco-Jarava
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Andrea Martín-Nalda
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Neus Baena
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Elisabeth Gabau
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Natàlia Padilla
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Xavier de la Cruz
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Ricardo Pujol-Borrell
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. David Comas
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Pere Soler-Palacín
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Manuel Hernández-González
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Roger Colobran.

    Ethics declarations

    Conflicts of Interest

    None of the authors has any potential financial conflict of interest related to this manuscript.

    Additional information

    Roger Colobran and Clara Franco-Jarava contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 3005 kb)

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark

    Cite this article

    Colobran, R., Franco-Jarava, C., Martín-Nalda, A. et al. Novel Mutations Causing C5 Deficiency in Three North-African Families. J Clin Immunol 36, 388–396 (2016). https://doi.org/10.1007/s10875-016-0275-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10875-016-0275-4

    Keywords

    • Complement system
    • complement 5 deficiency
    • meningococcal disease
    • mutation
    • African continental ancestry group