Properdin Deficiency

Properdin Deficiency of Alternative Pathway

Properdin is essential in stabilizing the complex of C3b with Bb, increasing the life span of C3bBb, a highly efficient C3-cleaving enzyme. Properdin deficiency leads to reduced function of the alternative pathway of complement activation. There have been over 100 reported cases of properdin deficiency. It is the only complement deficiency found to be inherited as an X-linked recessive trait. There are three reported types of properdin deficiency. The most common, type I, is a failure to synthesize properdin. Individuals with type I properdin deficiency are at a 250-fold increased risk of meningococcal sepsis. Type II and type III properdin deficiencies are extremely rare and result in minimally functional and nonfunctional abnormal properdin, respectively. Neisseria meningitidis is the most common pathogen encountered in properdindeficient individuals. Mortality from N. meningitidis runs very high in individuals with properdin deficiency at 34%-63%. Properdin deficiency has not been associated with autoimmunity.

All three forms of properdin deficiency are inherited in an X-linked manner and family studies have subsequently mapped the properdin gene to the short arm of the X-chromosome. Investigation into the molecular basis of properdin deficiency has revealed a marked degree of genetic heterogeneity even within geographically related families. The most common genetic basis in type I deficiency is a point mutation in exons 4-6, leading to the generation of a premature stop codon—this is exemplified by the large kindred described by Spath et al. in this issue and elsewhere. Normal mRNA transcription has been reported in one individual in the absence of detectable intracellular protein, suggesting that the truncated molecule is rapidly degraded.

All three variants of properdin deficiency are clinically characterized by a significant risk of meningococcal disease, particularly in association with unusual infective serotypes such as W-135 and Y. Infection with Neisseria meningitidis serogroup B has been reported less commonly and anecdotally seems to be associated with milder disease and good outcome, in accordance with the experience of Spath et al. reported here and elsewhere. Different defence mechanisms predominate against type B meningococcus (phagocytic killing) and atypical meningococcal serotypes (serum bactericidal activity), which may explain the differences in disease susceptibility and severity in properdin-deficient individuals.

Properdin Deficiency of Alternative Pathway Related Products

Properdin Deficiency of Alternative Pathway References

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