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A Large Family with a Gain-of-Function Mutation of Complement C3 Predisposing to Atypical Hemolytic Uremic Syndrome, Microhematuria, Hypertension and Chronic Renal Failure

Karl Lhotta^*,, Andreas R. Janecke, Johanna Scheiring, Barbara Petzlberger, Thomas Giner, Verena Fally, Reinhard Würzner^||, Lothar B. Zimmerhackl, Gert Mayer, and Veronique Fremeaux-Bacchi^¶

^* Department of Nephrology and Dialysis, Academic Teaching Hospital Feldkirch, Austria; Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck Medical University, Austria; Division of Clinical Genetics, Innsbruck Medical University, Austria; Department of Pediatrics I, Innsbruck Medical University, Austria; ^|| Department of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Austria; ^¶ Service d'Immunologie Biologique, Hopital Europeen Georges Pompidou, Paris, and INSERM UMRS 872, Cordeliers Research Center, Paris, France

Correspondence: Drive Karl Lhotta, Department of Nephrology and Hypertension, Academic Teaching Hospital Feldkirch, Carinagasse 47, A-6800 Feldkirch, Austria. Phone: +43 5522 303 2700; Fax +43 5522 303 7506; E-mail: Karl.lhotta{at}lkhf.at

Background and objectives: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in genes encoding complement-regulatory proteins factor H, I and B and membrane cofactor protein. Recently, heterozygous gain-of-function mutations in the complement C3 gene have been found in patients with aHUS.

Design, setting, participants, & measurements: A large family with a C3 R570Q mutation is described. Clinical and laboratory findings of carriers of the mutation and unaffected family members are reported.

Results: The index patient suffered from recurrent aHUS at age 22 and developed end-stage renal failure. Of 24 family members, nine harbored the C3 R570Q mutation. Carriers showed reduced or borderline C3 levels. Arterial hypertension was found in six family members, microhematuria in five and chronic kidney disease stage 3 in two elderly carrier patients. Despite marked consumption of C3, serum terminal complement complex levels were not elevated in carriers compared with other family members.

Conclusions: The penetrance of the C3 R570Q mutation to induce aHUS is incomplete and lower compared with mutations in other genes predisposing to the disease. The mutation is possibly also associated with hypertension, hematuria and chronic kidney disease, all of which may represent consequences of long-term complement activation in the renal vasculature.