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

Properdin type I deficiency is characterised by complete absence of extrace llular properdin, a positive regulator of the alternative pathway of comple ment activation. Properdin deficiency is associated with increased suscepti bility to severe meningococcal disease. We have identified the genetic defe ct in 10 Dutch families. Six different mutations and one sequence polymorph ism in the properdin gene were found. All amino acid substitutions were lim ited 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 foun d 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 regulatio n of properdin excretion apart from X-inactivation.