Sequence-based analysis of properdin deficiency: identification of point mutations in two phenotypic forms of an X-linked immunodeficiency.

Properdin deficiency is an inherited X-linked disorder causing increased susceptibility to meningococcal disease. Here, underlying genetic defects in the properdin gene were identified for the first time. Samples from individuals with type I deficiency, defined as complete absence of properdin in serum, and individuals with type II deficiency, characterized by low concentrations of properdin in serum, were analyzed by direct chromosome sequencing of overlapping PCR products. The complete gene, including 10 exons and 9 introns, covering 6460 bases of the region Xp11, was investigated by direct solid-phase sequencing. In the related individuals with type I deficiency a C to T mutation in exon 5 was identified, which gives rise to a stop codon TGA and thus a truncated gene product. In addition, point mutations were found in 4 introns and a silent mutation in exon 10. In the properdin gene from related individuals with type II deficiency two point mutations were found, one in intron 3 and one in exon 4. The latter mutation yields a substitution of arginine to tryptophan, which may affect folding, secretion, and/or turnover of the protein. The genetic and biochemical implications of these mutations are discussed.