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

Department of Medicine, Washington University in St. Louis, San Luis, Missouri, United States
Journal of the American Society of Nephrology (Impact Factor: 9.34). 08/2006; 17(7):2017-25. DOI: 10.1681/ASN.2005101051
Source: PubMed


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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    • "IFN-g production by murine CD4 + T cells is accompanied by specific metabolic changes (Chang et al., 2013), which led us to interrogate whether CD46 regulates human Th1 cell responses via modulation of key metabolic pathways. We used T cells from three patients with absent or severely reduced CD46 expression (CD46-1, CD46-2, and CD46-3 [Couzi et al., 2008; Fremeaux-Bacchi et al., 2006; and Figure S1B, legend]), T cells from healthy donors (HDs) in which CD46 protein expression was reduced by siRNA technique , and Jurkat T cell lines overexpressing specific CD46 isoforms . Whole-exome sequencing of DNA samples from patients CD46-2 (sibling of CD46-1) and CD46-3 confirmed the expected mutations in CD46 but did not identify additional mutations in candidate genes mediating T cell function or genes known to cause monogenic immune defects (Table S1 and S2). "
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    • "More than half of patients with aHUS have mutations in the genes involved in the alternative pathway of the complement system[5]. Mutations with loss-of-function of regulators (CFH, CFI, MCP and THBD)9101112and gain-offunction of key complement components (C3 and CFB)[13,14]have been found to predispose patients to the development of aHUS. A normal plasma level of complement proteins does not preclude the presence of mutations in these genes. "
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    • "Mutation screening of CFH, CFI, CD46, C3 and CFB revealed a heterozygous CD46 splice site mutation (IVS2+2T>G). This change has previously been identified in a patient with aHUS and demonstrated to result in abnormal splicing [6, 7]. FACS analysis of granulocytes from the patient demonstrated that cell surface expression of CD46 was reduced by 50% (Figure 1). "
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