Complement Factor D Deficiency

Factor D Deficiency of Alternative Pathway Background

Factor D is essential in catalyzing the cleavage of factor B to Bb, allowing Bb to associate with hydrolyzed C3 or C3b. Factor D deficiency is extremely rare. The most well studied family cluster of factor D deficiency in the Netherlands, with 21 heterozygotes available for study, describes low normal factor D levels and no clinical disease in heterozygotes, supporting autosomal recessive inheritance. Clinical disease from factor D deficiency occurs from a lack of alternative pathway hemolytic activity and greatly reduced opsonization of encapsulated bacteria. Invasive meningococcal infections have been seen in multiple individuals with factor D deficiency. Risk of infection with E. coli and Streptococcus pneumoniae is also increased. Factor D deficiency has not been associated with autoimmunity.

A complement factor D deficiency was found in a young woman who had experienced a serious Neisseria meningitidis infection, in a deceased family member with a history of meningitis, and in three relatives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils.

The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified factor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. The gene encoding factor D was found to contain a point mutation that changed the TCG codon for serine 42 into a TAG stop codon. This mutation was found in both alleles of the five completely factor D-deficient family members and in one allele of 21 other members of the same family who had decreased or low-normal factor D levels in their serum. The gene sequence of the signal peptide of human factor D was also identified. Our report is the first, to our knowledge, to document a Factor D gene mutation. The mode of inheritance of factor D deficiency is autosomal recessive, in accordance with the localization of the Factor D gene on chromosome 19. Increased susceptibility for infections in individuals with a partial factor D deficiency is unlikely.

Factor D Deficiency of Alternative Pathway Related Products

Factor D Deficiency of Alternative Pathway References

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