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Mutations in Complement Factor I Predispose to Development of Atypical Hemolytic Uremic Syndrome

David Kavanagh^*, Elizabeth J. Kemp^*, Elizabeth Mayland^*, Robin J. Winney, Jeremy S. Duffield, Graham Warwick, Anna Richards^*, Roy Ward^||, Judith A Goodship^* and Timothy H.J. Goodship^*

^* Institute of Human Genetics, University of Newcastle upon Tyne, United Kingdom; Department of Renal Medicine, Royal Infirmary, Edinburgh, United Kingdom; Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts; John Walls Renal Unit, University Hospitals of Leicester, Leicester, United Kingdom; and ^|| Department of Immunology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom

Address correspondence to: Dr. Timothy H.J. Goodship, Institute of Human Genetics, University of Newcastle upon Tyne, Tyne and Wear NE1 3BZ, UK. Phone: 44-191-241-8632; Fax: 44-191-241-8666; E-mail: t.h.j.goodship{at}newcastle.ac.uk

Received for publication January 25, 2005. Accepted for publication April 14, 2005.

Mutations in the plasma complement regulator factor H (CFH) and the transmembrane complement regulator membrane co-factor protein (MCP) have been shown to predispose to atypical hemolytic uremic syndrome (HUS). Both of these proteins act as co-factors for complement factor I (IF). IF is a highly specific serine protease that cleaves the -chains of C3b and C4b and thus downregulates activation of both the classical and the alternative complement pathways. This study looked for IF mutations in a panel of 76 patients with HUS. Mutations were detected in two patients, both of whom had reduced serum IF levels. A heterozygous bp change, c.463 G>A, which results in a premature stop codon (W127X), was found in one, and in the other, a heterozygous single base pair deletion in exon 7 (del 922C) was detected. Both patients had a history of recurrent HUS after transplantation. This is in accordance with the high rate of recurrence in patients with CFH mutations. Patients who are reported to have mutations in MCP, by contrast, do not have recurrence after transplantation. 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.

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