MOLECULAR CHARACTERIZATION OF PROPERDIN DEFICIENCY TYPE-III - DYSFUNCTION PRODUCED BY A SINGLE-POINT MUTATION IN EXON-9 OF THE STRUCTURAL GENE CAUSING A TYROSINE TO ASPARTIC-ACID INTERCHANGE

Inherited properdin deficiency is an X-linked recessive disorder clini cally manifested by susceptibility to meningococcal disease, Deficienc y of properdin is characterized by complete absence (type I), very low level presence (type II), or the presence of a dysfunctional properdi n protein in serum as found in one Dutch family (type III). To better understand the dysfunctional protein on the molecular level, samples f rom three members of the Dutch family were analyzed by direct genomic sequencing, The sequence of the complete gene, including 10 exons and 9 introns, covering about 6500 bases was determined, The dysfunctional properdin was found to be caused by a single T to G mutation in exon 9, which gives rise to a substitution of a tyrosine by an aspartic aci d residue at position 387. This change to a hydrophilic amino acid aff ects the function of the properdin molecule, although the oligomerizat ion of dysfunctional properdin molecules was similar to that of normal properdin, In binding studies with C3b and properdin in serum, no pro perdin deposition was detected with the type III deficient serum, Inhi bition studies with different decapeptides revealed distinct inhibitor y sequences, and indicated also that the part of properdin containing the type III mutation was not directly involved in the binding to C3b, The mutation most likely causes conformational changes that make the properdin molecule dysfunctional by affecting its binding to C3b.