TY - JOUR
T1 - Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome
AU - Fremeaux-Bacchi, Véronique
AU - Moulton, Elizabeth A.
AU - Kavanagh, David
AU - Dragon-Durey, Marie Agnès
AU - Blouin, Jacques
AU - Caudy, Amy
AU - Arzouk, Nadia
AU - Cleper, Roxanna
AU - Francois, Maud
AU - Guest, Genevieve
AU - Pourrat, Jacques
AU - Seligman, Roland
AU - Fridman, Wolf Herman
AU - Loirat, Chantal
AU - Atkinson, John P.
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33745812440&partnerID=8YFLogxK
U2 - 10.1681/ASN.2005101051
DO - 10.1681/ASN.2005101051
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 16762990
AN - SCOPUS:33745812440
SN - 1046-6673
VL - 17
SP - 2017
EP - 2025
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -