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Genetic and Functional Analyses of Membrane Cofactor Protein (CD46) Mutations in Atypical Hemolytic Uremic Syndrome

Véronique Fremeaux-Bacchi^*,, Elizabeth A. Moulton, David Kavanagh, Marie-Agnès Dragon-Durey^*, Jacques Blouin^*, Amy Caudy, Nadia Arzouk, Roxanna Cleper^||, Maud Francois^¶, Genevieve Guest^**, Jacques Pourrat, Roland Seligman, Wolf Herman Fridman^*,, Chantal Loirat and John P. Atkinson

^* Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Immunologie Biologique, and INSERM Unité 255, Centre de Recherches Biomeédicales des Cordeliers, Paris, France; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri; Assistance Publique-Hôpitaux de Paris, Service de Néphrologie, Hôpital Bicetre, France; ^|| Schneider Children’s Medical Center, Tel Aviv University, Tel Aviv, Israel; ^¶ Service de Néphrologie, CHU de Tours, Hôpital Bretonneau, Tours, France; ^** Assistance Publique-Hôpitaux de Paris, Service de Néphrologie pédiatrique, Hôpital Necker Enfants Malades, Paris France; Service de Néphrologie, CHU de Toulouse, Toulouse, France; Service de Pédiatrie, Centre Hospitalier du Luxembourg, Luxembourg, Luxembourg, and Assistance Publique-Hôpitaux de Paris, Service de Néphrologie Pédiatrique, Hôpital Robert-Debré, Paris, France

Address correspondence to: Dr. Véronique Fremeaux-Bacchi, Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75908 Paris cedex 15, France. Phone: 33-1-5609-3941; Fax: 33-1-5609-2080; E-mail: veronique.fremeaux-bacchi{at}hop.egp.ap-hop-paris.fr

Received for publication October 12, 2005. Accepted for publication April 23, 2006.

Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non–Shiga toxin–associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.

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