Novel Mutations Causing C5 Deficiency in Three North-African Families
- 262 Downloads
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.
KeywordsComplement system complement 5 deficiency meningococcal disease mutation African continental ancestry group
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.
Compliance with Ethical Standards
Conflicts of Interest
None of the authors has any potential financial conflict of interest related to this manuscript.
- 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.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.CrossRefPubMedPubMedCentralGoogle Scholar