Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome.
S. Hakobyan, A. Tortajada, C. L. Harris, S. Rodriguez de Cordoba and B. P. Morgan. Kidney International 2010, 78:782.
Complement factor H mutations responsible for aHUS:
The complement system is a major mechanism of innate immunity that serves to link recognition of microbes to effector functions and to the development of inflammation. Complement is implicated in numerous diseases; for example, atypical hemolytic uremic syndrome (aHUS) is associated with complement alternative pathway defects in over 50% of cases. Mutations in factor H (fH) gene (CFH), the major regulator of complement alternative pathway, are most common in aHUS. In some aHUS cases, null mutations in CFH are found, resulting in heterozygous deficiency of fH. Although patients with null mutations in heterozygosity will usually have low plasma levels of fH, the large variability in fH concentrations in normal individuals often makes it impossible to identify cases simply by measuring fH levels in plasma.
Polymorphism Y402H useful marker for individual CFH alleles:
A common polymorphism in fH, Y402H, is strongly associated with another disease, macular degeneration. We have generated two novel anti-fH monoclonal antibodies MBI-6 and MBI-7, specific to Y402 and H402 alleles respectively. We have developed robust assays based on these antibodies that allow us to individually quantify Y402 and H402 alleles. Y402H is the most common polymorphism in fH and over 40% of Caucasians are Y402H heterozygous. This polymorphism therefore represents a useful “marker” for individual CFH alleles. Although the Y402H polymorphism has no apparent direct link to aHUS, application of the new assays to aHUS families enabled us to identify, characterize and confirm new CFH alleles associated with low or no expression of fH and show that these low/no expression alleles conferred strong predisposition to aHUS. These novel tools will not only help identify the molecular basis of disease in patients with aHUS, but also aid prediction of risk in their relatives.
Conclusion:
The complement system plays an important role in diverse diseases; these novel reagents and assays will be useful in unambiguous and rapid identification of occult low/no expression CFH alleles.