Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies

Abstract

Properdin type I deficiency is characterised by complete absence of extracellular properdin, a positive regulator of the alternative pathway of complement activation. Properdin deficiency is associated with increased susceptibility to severe meningococcal disease. We have identified the genetic defect in 10 Dutch families. Six different mutations and one sequence polymorphism in the properdin gene were found. All amino acid substitutions were limited to conserved amino acids in exons 7 and 8 in contrast to the premature stops that were found in other exons. The missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolised intracellularly. The decreased properdin levels found in some healthy females carrying one mutated properdin gene were studied for X-inactivation. Most carriers with extreme low or high properdin levels showed preferential X-inactivation for the normal or mutated X chromosome, respectively. We observed some exceptions, suggesting additional regulation of properdin excretion apart from X-inactivation.

The alternative complement pathway revisited

“…Properdin deficiency was first described in a Swedish family in association with fulminant meningococcal disease [87]. In type I deficiency with complete absence of circulating properdin inherited as an X‐linked recessive disorder [35–37], distinct mutations have been demonstrated in exon 4, 5, 6, 8 and 10 of the properdin gene.…”

“…To generate properdin knockout mice, Kimura et al targeted exon 3-5 of the properdin gene for disruption [28] because mutations in exon 4-6 of the human properdin gene are among those associated with type I properdin deficiency with absence of circulating properdin [35][36][37]. In properdin Ϫ/Ϫ mice, Northern blots showed absence of properdin mRNA and Western blots confirmed lack of properdin protein in plasma.…”

Epidemiologic and Microbiologic Characteristics of Recurrent Bacterial and Fungal Meningitis in The Netherlands, 1988–2005

“…In contrast, the proportion of cases due to the rare serogroups W135, Y, and Z among 99 episodes of recurrent meningococcal disease was higher than that among the episodes of nonrecurrent meningococcal disease, whereas serogroups A and 29E were only seen in cases of nonrecurrent meningitis. Patients with recurrent meningococcal disease may have defects in the complement system [46][47][48][49]. At least 13 of these 99 episodes occurred in 6 individuals with a complement defect [50].…”

A Gain-of-Function Mutation inNALCNin a Child with Intellectual Disability, Ataxia, and Arthrogryposis

“…CFP (MIM# 300383) encodes properdin, a plasma glycoprotein that regulates the alternative complement pathway of the innate immune system and whose mutations have been implicated in X‐linked properdin deficiency resulting in high susceptibility to meningococcal infections [van den Bogaard, et al., ]. Because of the apparent lack of requirement of CFP for brain development or function, we did not further consider the variant in this gene as a candidate.…”