title: Compound heterozygous mutations in the C6 gene of a child with recurrent infections.
abstract: 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.
authors.affiliation: Department of Pediatric Nephrology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Dineke.Westra@radboudumc.nl.
authors.forename: Dineke
authors.initials: D
authors.lastname: Westra
authors.affiliation: Department of Pediatric Infectious Diseases & Immunology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Roel.Kurvers@radboudumc.nl.
authors.forename: Roel A J
authors.initials: RA
authors.lastname: Kurvers
authors.affiliation: Department of Pediatric Nephrology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Pediatrics, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Bert.vandenHeuvel@radboudumc.nl.
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Division of Hygiene & Medical Microbiology, Innsbruck Medical University, 6020 Innsbruck, Austria. Electronic address: reinhard.wuerzner@i-med.ac.at.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Würzner
authors.affiliation: Department of Pediatric Rheumatology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Esther.Hoppenreijs@radboudumc.nl.
authors.forename: Esther P A H
authors.initials: EP
authors.lastname: Hoppenreijs
authors.affiliation: Department of Pediatric Infectious Diseases & Immunology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Nijmegen Institute for Infection, Immunity and Inflammation (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Michiel.vanderFlier@radboudumc.nl.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
authors.affiliation: Department of Pediatric Nephrology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Nicole.vandeKar@radboudumc.nl.
authors.forename: Nicole C A J
authors.initials: NC
authors.lastname: van de Kar
authors.affiliation: Department of Pediatric Infectious Diseases & Immunology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Nijmegen Institute for Infection, Immunity and Inflammation (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Adilia.Warris@radboudumc.nl.
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
mesh_terms: D001170:Arthritis, Infectious / Q000235:genetics* / Q000382:microbiology / Q000821:virology; D003183:Complement C6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D012008:Recurrence
chemical_list: D003183:Complement C6
keywords: C-reactive protein; C6; C6SD; CRP; Complement system; ELISA; ESR; Genetic defects; MAC; Recurrent infections; SNP; Subtotal C6 deficiency; TCC; complement component 6; enzyme-linked immunosorbent assay; erythrocyte sedimentation rate; membrane attack complex; single nucleotide polymorphism; subtotal C6 deficiency; terminal complement complex