title: 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.
abstract: Inherited properdin deficiency is an X-linked recessive disorder clinically manifested by susceptibility to meningococcal disease. Deficiency of properdin is characterized by complete absence (type I), very low level presence (type II), or the presence of a dysfunctional properdin protein in serum as found in one Dutch family (type III). To better understand the dysfunctional protein on the molecular level, samples from 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 acid residue at position 387. This change to a hydrophilic amino acid affects the function of the properdin molecule, although the oligomerization of dysfunctional properdin molecules was similar to that of normal properdin. In binding studies with C3b and properdin in serum, no properdin deposition was detected with the type III deficient serum. Inhibition studies with different decapeptides revealed distinct inhibitory 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.
authors.affiliation: Department of Medical Microbiology, Lund University, Sweden.
authors.forename: G N
authors.initials: GN
authors.lastname: Fredrikson
authors.forename: J
authors.initials: J
authors.lastname: Westberg
authors.forename: E J
authors.initials: EJ
authors.lastname: Kuijper
authors.forename: C C
authors.initials: CC
authors.lastname: Tijssen
authors.forename: A G
authors.initials: AG
authors.lastname: Sjöholm
authors.forename: M
authors.initials: M
authors.lastname: Uhlén
authors.forename: L
authors.initials: L
authors.lastname: Truedsson
mesh_terms: D000595:Amino Acid Sequence; D003176:Complement C3 / Q000378:metabolism; D005091:Exons; D005796:Genes; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008589:Meningococcal Infections / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011414:Properdin / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017421:Sequence Analysis; D014960:X Chromosome / Q000235:genetics
chemical_list: D003176:Complement C3; D009842:Oligopeptides; D011414:Properdin