BACKGROUND AND OBJECTIVES:Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort.METHODS:We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2.RESULTS:The median (range) age at onset of NS was 11 (1-72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2.CONCLUSIONS:PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.

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 Biomédicales des Cordeliers, Paris, France; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri; Assistance PubliqueHôpitaux 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

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.