Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding.
SourcePediatric Nephrology, 27, 9, (2012), pp. 1519-1524
1 september 2012
Article / Letter to editor
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Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders NCMLS 4: Energy and redox metabolism; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder; IGMD 9: Renal disorder NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder NCMLS 5: Membrane transport and intracellular motility; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder NCMLS 5: Membrane transport and intracellular motility
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations affecting complement proteins and regulators and with autoantibodies against complement factor H (CFH). Approximately half of the aHUS patients progress to end-stage renal disease. DNA analysis of the risk factor genes is important for prognosis of aHUS recurrence after renal transplantation. METHODS: Mutational screening of C3 encoding the central complement component was performed by Sanger sequencing in 70 aHUS patients. Mutated and wild type recombinant C3b proteins were produced and their affinity to CFH was analyzed by ELISA. RESULTS: A single novel missense change p.Lys65Gln in C3 was found in 3 aHUS patients. The alteration leads to decreased binding of C3b to CFH in vitro. All three patients acquired the illness as adults and had a first aHUS episode after renal transplantation or suffered recurrence of the disease after transplantation. CONCLUSIONS: The novel C3 change was found in 3 aHUS patients. It results in decreased C3b binding to CFH and thus might lead to impaired C3b inactivation in vivo. The p.Lys65Gln is likely to be associated with aHUS after kidney transplantation and, therefore, might be an important prognostic factor.
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