title: Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections.
abstract: The complement system is an essential element in our innate defense against infections with Neisseria meningitidis. We describe 2 cases of meningococcal septic shock, 1 of them fatal, in 2 children of a Turkish family. In the surviving patient, alternative pathway activation was absent and factor D plasma concentrations were undetectable. Concentrations of mannose-binding lectin (MBL), C1q, C4 and C3, factor B, properdin, factor H, and factor I were normal. Mutation analysis of the factor D gene revealed a T638 > G (Val213 > Gly) and a T640 > C (Cys214 > 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.
authors.affiliation: Department of General Internal Medicine, Pediatrics and Intensive Care, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Sprong
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Corry
authors.initials: C
authors.lastname: Weemaes
authors.forename: Chris
authors.initials: C
authors.lastname: Neeleman
authors.forename: Christel L M
authors.initials: CL
authors.lastname: Geesing
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
authors.forename: Marcel
authors.initials: M
authors.lastname: van Deuren
mesh_terms: D019943:Amino Acid Substitution / Q000276:immunology; D015922:Complement C1q / Q000032:analysis / Q000235:genetics / Q000276:immunology; D050577:Complement C3-C5 Convertases / Q000032:analysis / Q000235:genetics / Q000276:immunology; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology; D011416:Complement Factor D / Q000032:analysis / Q000172:deficiency* / Q000627:therapeutic use; D003170:Complement Pathway, Alternative / Q000235:genetics* / Q000276:immunology; D004252:DNA Mutational Analysis; D005260:Female; D030342:Genetic Diseases, Inborn / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008589:Meningococcal Infections / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D009345:Neisseria meningitidis / Q000276:immunology; D017354:Point Mutation / Q000276:immunology; D012772:Shock, Septic / Q000097:blood / Q000235:genetics* / Q000276:immunology
chemical_list: D015922:Complement C1q; D050577:Complement C3-C5 Convertases; D011416:Complement Factor D; D011415:Complement Factor B