T H J Goodship

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..We conclude that expression of CLC-5 in mIMCD-3 cells allows acidification of endosomes and endocytosis, and that disruption of CLC-5 expression causes abnormal crystal agglomeration...

..The report of Licht et al. of a mutation in the complement-regulatory N-terminal region of Factor H in MPGN II provides additional insight into the pathogenesis of this condition...

..Antibody depleting therapy may have a role in such patients and we suggest that screening for factor H autoantibodies should be undertaken in all patients with MPGN...

..In the other two, a substitution (S206P) resulted in cell-surface expression but inefficient inactivation of surface-bound C3b. These findings provide further evidence that complement dysregulation predisposes to the development of HUS...

..Most could be referred back to their general practitioner for long-term follow-up...

..In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation...

..In conclusion, in this small series of aHUS patients we found no evidence that fB has a major role in the pathogenesis of aHUS...

..Many different predisposing genetic factors resulting in complement overactivation have been described in aHUS. Additionally, autoantibodies against complement regulatory proteins have been reported...

..This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies...

..The analysis of genetic variation in complement genes is a promising tool to unravel mechanisms of host-pathogen interaction and can provide new insights into the evolution of the human immune system...

..All the patients had a normal serum factor H concentration. In this small cohort of IgA nephropathy patients we have not found evidence to support the hypothesis that factor H is a major susceptibility factor for the disease...

..In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS...

..As with CFH- and MCP-associated HUS, there was incomplete penetrance in the family of one of the affected individuals. This study provides further evidence that atypical HUS is a disease of complement dysregulation...

..We recommend consideration of complement gene mutations in any patient with HUS after a diarrheal episode in which there are unusual features...

..Combined liver/kidney transplantation for patients known to have a CFH mutation has not been successful to date. There is optimism that in the future, targeted complement inhibitors will be of major therapeutic benefit in this condition...

..These recent advances will lead to logical, targetted changes in the management of these conditions...

..The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations...

..Neither family has a factor H mutation. This report underlines the risk of disease recurrence in recipients associated with live-related renal transplantation in HUS and also suggests that the donors may be at risk...

..The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes...

..Three of the patients carry also mutations in membrane cofactor protein and factor H strengthening the hypothesis that individuals may carry multiple susceptibility factors with an additive effect on the risk of developing aHUS...

..A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders...

..Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS...

..Long-term tolerance and efficacy of such intensive plasma therapy are still unknown. Reported secondary failure of plasma therapy in factor H deficiency warrants the search for alternative therapeutic approaches...

..As the remaining FH substitutions could also be correlated with their proximity to conserved basic residues, haemolytic uraemic syndrome may result from a failure of FH to interact with polyanions at cell surfaces in the kidney...

..This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH...

..Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis...

..Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transmembrane proteins in situ...

..It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence...

..This patient demonstrates that HUS can recur in a kidney transplant without the diagnostic hematological features and emphasizes the need for early transplant biopsy in such patients showing a decline in transplant function...

..The feasibility of kidney transplantation in case of atypical HUS related to factor H mutation using continuous prophylactic PE intensified during relapses should be confirmed in prospective studies...

..73 m2 [1.98 mL/s/1.73 m2]) on maintenance PE therapy. In conclusion, the response to treatment of these monozygotic twins suggests that long-term PE may have benefits over plasma infusion alone...

..We, therefore, provide conclusive evidence that gene conversion is responsible for functionally significant CFH mutations in aHUS...

..This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS...

..Discovery of these mutations has revealed important genotype-phenotype correlations. MCP-HUS has a better prognosis and a better outcome after transplantation than either CFH-HUS or IF-HUS...

..The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches...

..The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS...

..Renal and uterine abnormalities have not been described in families without early-onset diabetes...