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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4865-4870. Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-07-2820. This Article Full Text (PDF) All Versions of this Article: 2005-07-2820v1 107/12/4865    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sprong, T. Articles by van Deuren, M. Search for Related Content PubMed PubMed Citation Articles by Sprong, T. Articles by van Deuren, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 15, 2005 Accepted February 15, 2006 Deficient alternative complement pathway activation due to factor D deficiency by two novel mutations in the Complement Factor D gene in a family with meningococcal infections Tom Sprong, Dirk Roos, Corry Weemaes, Chris Neeleman, Christel L Geesing, Tom E Mollnes, and Marcel van Deuren* Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen University Centre for Infectious Diseases, Nijmegen, The Netherlands Sanquin Research at CLB, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Intensive Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Pediatrics, Bernhoven Hospital, Oss, The Netherlands Institute of Immunology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands * Corresponding author; email: m.vandeuren{at}aig.umcn.nl. The complement system is an essential element in our innate defense against infections with N. meningitidis. We describe two cases of meningococcal septic shock, one of them fatal, in two children of a Turkish family. In the surviving patient, alternative pathway activation was absent and factor D plasma concentrations were undetectable. Concentration of MBL, C1q, C4 and C3, Factor B, Properdine, factor H and I were normal. Mutation analysis of the factor D gene revealed a T638 >G (Val213 >Gly) and a T640 >C (Cys 214>Arg) mutation in the genomic DNA from the patient, both in homozygous form. The consanguineous parents and an unaffected sister had these mutations in heterozygous form. In vitro incubation of factor-D-deficient plasma of the boy with serogroup B N. meningitidis, showed normal MBL-mediated complement activation but no formation of the alternative pathway C3-convertase C3bBbP, and severely decreased C3bc formation and terminal complement activation. The defect was restored after supplementation with factor D. In conclusion, this is the second report of a factor D gene mutation leading to factor D deficiency in a family with meningococcal disease. This deficiency abolishes alternative-pathway dependent complement activation by N. meningitidis, and leads to an increased susceptibility to invasive meningococcal disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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