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Wilson C.,Institute of Transplantation | Torpey N.,Addenbrookes Hospital | Jaques B.,Institute of Transplantation | Strain L.,Northern Molecular Genetics Service | And 4 more authors.
American Journal of Kidney Diseases | Year: 2011

Atypical hemolytic uremic syndrome was diagnosed in a 62-year-old man. Sequencing of the CFH gene, which encodes complement factor H, revealed a heterozygous adenine to guanine mutation at nucleotide 3550 of the complementary DNA, leading to a predicted substitution of alanine for threonine at amino acid position 1184 in the protein (c.3550A>G, p.Thr1184Ala). Three years later, he received a simultaneous liver-kidney transplant with plasmapheresis and intratransplant plasma infusion. The postoperative course was complicated by an anastomotic biliary stricture that was treated successfully using endoscopic stenting. One year later, he has excellent function of both transplants, emphasizing that simultaneous liver-kidney transplant is a valuable treatment option in the management of adult patients with atypical hemolytic uremic syndrome. © 2011 National Kidney Foundation, Inc.

Holmes L.V.,Northumbria University | Strain L.,Northern Molecular Genetics Service | Staniforth S.J.,Northumbria University | Moore I.,Northumbria University | And 5 more authors.
PLoS ONE | Year: 2013

In this study we have used multiplex ligation-dependent probe amplification (MLPA) to measure the copy number of CFHR3 and CFHR1 in DNA samples from 238 individuals from the UK and 439 individuals from the HGDP-CEPH Human Genome Diversity Cell Line Panel. We have then calculated the allele frequency and frequency of homozygosity for the copy number polymorphism represented by the CFHR3/CFHR1 deletion. There was a highly significant difference between geographical locations in both the allele frequency (X2 = 127.7, DF = 11, P-value = 4.97x10-22) and frequency of homozygosity (X2 = 142.3, DF = 22, P-value = 1.33x10-19). The highest frequency for the deleted allele (54.7%) was seen in DNA samples from Nigeria and the lowest (0%) in samples from South America and Japan. The observed frequencies in conjunction with the known association of the deletion with AMD, SLE and IgA nephropathy is in keeping with differences in the prevalence of these diseases in African and European Americans. This emphasises the importance of identifying copy number polymorphism in disease. © 2013 Holmes et al.

Ermini L.,Northumbria University | Goodship T.H.J.,Northumbria University | Strain L.,Northern Molecular Genetics Service | Weale M.E.,Kings College London | And 4 more authors.
Molecular Immunology | Year: 2012

It is well established that common genetic variants in CFH, CD46 and the CFHRs are additional risk factors for the development of aHUS. To examine the hypothesis that common variants in other complement genes have a similar effect we genotyped 501 SNPs in 47 complement genes in 94 aHUS patients from Newcastle, 126 aHUS patients from Paris, 374 UK controls and 165 French controls. We replicated the associations in CFH, CD46 and the CFHRs but found no association with any other complement gene. The strongest associations replicated in both cohorts were found for four SNPs within CD46 (p-value<10-3) and five SNPs within CFH (p-value<5×10-3). Significant replicable associations with single SNPs in CFHR2, CFHR4 and an intergenic SNP (CR1-CD46) were also found. Analysis of the Paris cohort showed that the association with CD46 SNPs was only present in those patients with complement mutations. Haplotype analysis showed at-risk and protective haplotypes in both CD46 and CFH. The CD46 haplotype was only disease-associated in those patients with mutations. © 2011 Elsevier Ltd.

Roumenina L.T.,French Institute of Health and Medical Research | Roumenina L.T.,University of Paris Descartes | Roumenina L.T.,University Pierre and Marie Curie | Rybkine T.,French Institute of Health and Medical Research | And 19 more authors.
Blood | Year: 2015

The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 a HUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity. © 2015 by The American Society of Hematology.

Bento D.,Intensive Care Unit | Mapril J.,Intensive Care Unit | Rocha C.,Intensive Care Unit | Marchbank K.J.,Northumbria University | And 5 more authors.
Renal Failure | Year: 2010

We report a case of atypical hemolytic uremic syndrome (aHUS) triggered by influenza A (H1N1) in a 17-year-old boy with a mutation in the gene (CD46) encoding the transmembrane complement regulator membrane cofactor protein. The patient recovered completely following treatment with oseltamivir, plasma exchange, and hemodialysis. We describe the case and discuss this unusual association of diseases. © Informa UK, Ltd.

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