Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH).

Many of the complement regulatory genes within the RCA cluster (1q32) have arisen through genomic duplication and the resulting high degree of sequence identity is likely to predispose to gene conversion events. The highest degree of identity is between the genes for factor H (CFH) and five factor H‐related proteins – CFHL1, CFHL2, CFHL3, CFHL4, and CFHL5. CFH mutations are associated with atypical hemolytic uremic syndrome (aHUS). In the Newcastle cohort of 157 aHUS patients we have identified CFH mutations in 25 families or individuals. Eleven of these 25 independent mutations are either c.3226C>G,Q1076E; c.3572C>T,S1191L; c.3590T>C,V1197A or combined c.3572C>T,S1191L/c.3590T>C,V1197A. Sequence analysis shows that all four of these changes could have arisen as a result of gene conversion between CFH and CFHL1. Analysis of parental samples in two patients with S1191L/V1197A has shown that the changes are de novo thus providing conclusive evidence that gene conversion is the mutational mechanism in these two cases. To confirm that S1191L and V1197A are disease predisposing we examined their functional significance in three ways – analysis of the C3b/C3d binding characteristics of recombinant mutant S1191L/V1197A protein, heparin affinity chromatography and haemolytic assays of serum samples from aHUS patients carrying these changes. The results showed that these changes resulted in impaired C3b binding and a defective capacity to control complement activation on cellular surfaces. We, therefore, provide conclusive evidence that gene conversion is responsible for functionally significant CFH mutations in aHUS. © 2006 Wiley‐Liss, Inc.

As the underlying disease mechanisms of TMA are now being better understood new options for a more precise diagnosis, improved therapy and prognosis for kidney transplantation become available for the benefit of patients. Here we summarize the recent developments in this rapidly progressing field.

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A feedback interference cancellation circuit is presented that uses a control loop to reject blockers in wireless receivers. The concept is based on a feedback translational loop which subtracts a blocker replica from the original blocker signal. In contrast to feedforward methods loop selectivity does not depend on exact gain matching of two paths but on the open loop gain which is easier to adjust. The concept is described including the theoretical derivations of the transfer function and stability. Nonidealities like I/Q mismatch and noise mechanisms are discussed. Finally, measurements from a prototype chip in 65-nm CMOS are presented showing the feasibility of active feedback cancellation. In a desensitization scenario, gain drops by more than 12 dB for a 15 dBm blocker at 20 MHz offset without feedback interference cancellation while a gain degradation of merely 3 dB is measured with feedback interference cancellation enabled.

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