Compound heterozygous mutations in the C6 gene of a child with recurrent infections

Dineke Westra, Roel A J Kurvers, Lambert P van den Heuvel, Reinhard Würzner, Esther P A H Hoppenreijs, Michiel van der Flier, Nicole C A J van de Kar, Adilia Warris

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


The complement system plays an important role in both the innate and adaptive immune system. Patients with inherited complement deficiencies have an increased risk of systemic bacterial infections. Deficiencies of the terminal complement pathway are especially associated with invasive meningococcal disease. Here, we report a case of a boy that presented with arthritis and recurrent bacterial and viral infections. Extensive analyses revealed decreased complement activity of both classical and alternative pathway, indicating a deficiency of C3 or one of the factors of the terminal complement pathway. Mutational analysis of the C6 gene identified two compound heterozygous mutations. An unknown missense aberration was found that involves the loss of a cysteine, possibly affecting the 3D structure of the protein. Furthermore, a known splice site variation was identified that results in a 14% shorter protein, due to transcription of amino acids that are normally intronic until a stop codon is reached (exon-intron boundary defect). It is known that the protein with this latter aberration is still functionally active when present with other C6 mutations and therefore, the consequences of the combination of the identified variations have been studied. Quantitative ELISAs showed that at least one allele produced a circulating C6 molecule that can be incorporated in the membrane attack complex, likely the truncated protein. In the present case we observed relapsing bacterial and viral infections, but no meningococcal disease. The reduced complement activity can be explained by the identified genetic variations in C6, as recombinant C6 supplementation corrected complement function in vitro.

Original languageEnglish
Pages (from-to)201-205
Number of pages5
JournalMolecular Immunology
Issue number2
Early online date30 Dec 2013
Publication statusPublished - Apr 2014

Bibliographical note

We would like to thank Rolando Colonia Silva (Innsbruck) for technical assistance.

In the present communication, DW and RK are responsible for experimental set-up and performance, for analysis and interpretation of the data, and for writing the manuscript. RW provided valuable expertise for the C6 ELISAs and contributed to revising the article. EH, MF, and AW are the treating physicians of the patient, provided patient information, and are responsible for revising the manuscript. AW further contributed to the experimental set-up, interpretation of obtained results, writing, and editing of the manuscript, together with NK and LH.

DW is supported by the Dutch Kidney Foundation (C09.2313).


  • Complement system
  • Genetic defects
  • Recurrent infections
  • Subtotal C6 deficiency


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