Timothy H J Goodship

Newcastle University, Newcastle-on-Tyne, England, United Kingdom

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Publications (187)1120.7 Total impact

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    ABSTRACT: Background: Differentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopaenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS-13 activity. The identification of alternative complement pathway abnormalities in atypical haemolytic uraemic syndrome, along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS. Objectives: We describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs. Patients/methods: 14 consecutive aHUS patients were screened for mutations in C3, CD46, CFH, CFI and CFB, as well as factor H antibodies. All aHUS patients had ADAMTS-13 activity above 10%. Results: 11/14 (79%) aHUS patients had platelet counts below 30 x 10(9) /l during the acute phase. Median presenting creatinine was 295 μmol/l whilst 5/14 (36%) presented with a serum creatinine level below 200 μmol/l. Alternative complement pathway mutations were detected in 9/14 (64%) patients, including CD46 mutations in 5/14 (36%). Patients were identified with novel mutations in CFB and C3 that have not been previously reported. Conclusions: We demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations may mimic TTP. ADAMTS-13 activity >10% in a patient with a TMA should necessitate genetic screening for complement abnormalities. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.
    Preview · Article · Oct 2015 · Journal of the American Society of Nephrology
  • Z Iqbal · K Wood · V Carter · T.H. Goodship · A.L. Brown · N.S. Sheerin
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    ABSTRACT: Atypical hemolytic uremic syndrome is a rare disease associated with genetic or acquired defects in complement regulation which frequently leads to renal failure. Disease often recurs early after kidney transplantation, leading to a rapid irreversible loss of function. Extrarenal features, such as hemolysis and thrombocytopenia, may not always occur, and diagnosis is made by demonstrating the classic features of thrombotic microangiopathy on renal biopsy. Eculizumab, a terminal complement inhibitor, has been used successfully to treat fulminant early recurrent disease after transplantation. We describe a case of disease recurrence presenting in the second year after transplantation with a gradual decline in function and the first report of eculizumab treatment for chronic thrombotic microangiopathy in a transplanted kidney. The resultant diagnostic challenges and successful response to eculizumab in this setting are discussed.
    No preview · Article · Sep 2015 · Transplantation Proceedings
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    Troels Ring · Birgitte Bang Pedersen · Giedrius Salkus · Timothy H.J. Goodship
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    ABSTRACT: IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg. He responded rapidly to this treatment and has had a stable creatinine around 150 µmol/L (1.67 mg/dL) for >6 months. However, proteinuria was unabated on maximal conventional anti-proteinuric treatment, and a repeat renal biopsy 11 months after presentation revealed severe chronic changes. We believe this case provides proof of principle that complement inhibition may be beneficial in IgAN but also that development of chronicity may be independent of complement.
    Preview · Article · Aug 2015 · CKJ: Clinical Kidney Journal
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    ABSTRACT: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · The American Journal of Human Genetics
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    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system, leading to complement overactivation. A humanized anti-C5 monoclonal antibody, eculizumab, has been available for the treatment of aHUS since 2011. The long-term safety and efficacy of this novel drug in the pediatric population remain under review. We present a child with a hybrid CFH/CFHR3 gene who, having had multiple disease relapses despite optimal treatment with plasma exchange, commenced eculizumab therapy in August 2010. She remains relapse free in follow-up at 52 months, and treatment has been well tolerated. The risk of meningococcal disease during this treatment is recognized. Despite vaccination against meningococcal disease and appropriate antibiotic prophylaxis, our patient developed meningococcal bacteremia 30 months into treatment. She presented with nonspecific symptoms but recovered without sequelae with appropriate treatment. We recommend that children be vaccinated against invasive meningococcal infection before beginning eculizumab therapy and take appropriate antibiotic prophylaxis during treatment, and we suggest that vaccine responses should be checked and followed annually. Clinicians need to maintain a high index of suspicion for invasive meningococcal disease. Neither vaccination nor antibiotic prophylaxis provides complete protection in patients on eculizumab therapy. The appropriate dosage of eculizumab needed to achieve remission in aHUS in the pediatric population is unknown. Having achieved remission in our patient, we monitor eculizumab and CH50 levels to evaluate ongoing blockade of the terminal complement cascade. Such information may help guide dosing intervals in the future. Copyright © 2015 by the American Academy of Pediatrics.
    Full-text · Article · May 2015 · PEDIATRICS
  • Edwin Wong · Rachel Challis · Neil Sheerin · Sally Johnson · David Kavanagh · Timothy H J Goodship
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    ABSTRACT: Approximately 50% of aHUS patients have an underlying inherited and/or acquired abnormality of complement which predisposes to excessive activation of the alternative pathway. Use of complement inhibitors such as eculizumab to treat aHUS is therefore logical. Anecdotal reports and subsequent open-label trials demonstrated the efficacy of eculizumab in aHUS leading to approval by both the FDA and EMA. NHS England established in 2013 an interim national service for aHUS including funding for eculizumab for both new patients and those undergoing transplantation. NICE guidance now also recommends eculizumab for funding within the NHS in England under the coordination of an expert centre. The investigation and response to treatment in this cohort provides a unique resource for patient stratification. Copyright © 2015 Elsevier GmbH. All rights reserved.
    No preview · Article · May 2015 · Immunobiology
  • Neil Sheerin · David Kavanagh · Timothy H J Goodship · Sally Johnson
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    ABSTRACT: In 2013 NHS England commissioned the use of eculizumab for both new patients with aHUS and those undergoing transplantation. This national service is delivered locally but coordinated by an expert centre at the Newcastle upon Tyne Hospitals NHS Foundation Trust. In the first year of the service 43 aHUS patients received eculizumab, 15 children and 28 adults. 23 were new patients and 20 prevalent. 15 of the 23 new patients required dialysis before eculizumab was started, 8 of these recovered renal function. 12 of the 20 prevalent patients who received eculizumab were transplant patients, 8 with prophylactic use and 4 for recurrent disease; the outcome in all was good. Eculizumab was withdrawn in 14 patients, 5 were patients who had not recovered renal function. In 3 of the 14 patients it was necessary to reintroduce eculizumab because of recurrent disease (2 extra-renal and 1 renal). There were 2 deaths in the 43 patients, neither was associated with use of eculizumab. There were no episodes of meningococcal disease. The establishment of this national service has enabled aHUS patients in England to receive eculizumab when they need it for as long as they need it. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Apr 2015 · QJM: monthly journal of the Association of Physicians
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    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.Kidney International advance online publication, 4 February 2015; doi:10.1038/ki.2014.423.
    Full-text · Article · Feb 2015 · Kidney International

  • No preview · Conference Paper · Oct 2014
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    ABSTRACT: Background Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence—early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. Methods We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. Results and Conclusions We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.
    No preview · Article · Sep 2014 · Journal of Medical Genetics
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    ABSTRACT: Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS
    No preview · Article · Aug 2014 · Journal of the American Society of Nephrology
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    ABSTRACT: Autoantibody formation against Factor H (FH) is found in 7-10% of patients who are diagnosed with atypical haemolytic uraemic syndrome (aHUS). These autoantibodies predominately target the C-terminal cell binding recognition domain of FH and are associated with absence of FHR1. Additional autoantibodies have also been identified in association with aHUS, for example autoantibodies to Factor I. Based on this, and that there are genetic mutations in other complement regulators and activators associated with aHUS, we hypothesised that other complement regulator proteins, particularly surface bound regulators in the kidney, might be the target for autoantibody formation in aHUS. Therefore, we assayed serum derived from 89 patients in the Newcastle aHUS cohort for the presence of autoantibodies to CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF), CD35 (complement receptor type 1, CR1; TP10) and CD59. We also assayed 100 healthy blood donors to establish the normal levels of reactivity towards these proteins in the general population. Recombinant proteins CD46 and CD55 (purified from Escherichia coli) as well as soluble CR1 (CD35) and oligomeric C4BP-CD59 (purified from eukaryotic cell media) were used in ELISA to detect high responders. False positive results were established though Western blot and flow cytometric analysis. After excluding false positive responders to bacterial proteins in the CD46 and CD55 preparations, and responses to blood group antigens in CD35, we found no significant level of patient serum IgG reactivity with CD46, CD55, CD35 or CD59 above that detected in the normal population. These results suggest that membrane anchored complement regulators are not a target for autoantibody generation in aHUS.
    No preview · Article · Aug 2014 · Molecular Immunology
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    ABSTRACT: We present a case of haemolytic uraemic syndrome (HUS) triggered by Shigella flexneri. Of the Shigella species, only S. dysenteriae type 1 is said to produce Shiga toxin and consequently cause HUS. Investigation of the complement system in this patient revealed a CD46 mutation. In individuals with mutations in complement genes incomplete penetrance of atypical HUS (aHUS) is seen, suggesting that a trigger, such as infection, is required for disease to manifest. In an era of complement modulatory therapy for aHUS it is important to be alert to unusual presentations of diarrhoeal-associated disease.
    Full-text · Article · Jun 2014 · CKJ: Clinical Kidney Journal
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    ABSTRACT: Introduction and Aims: In hemodialysis (HD) patients low pre-HD serum sodium (SNa+) and high Na+ gradients have been associated with higher mortality. Increased pre-HD SNa+ variability has been linked to mortality, while stable SNa+ levels are associated with better survival. Here we investigated the joint relationship of SNa+ variability (expressed as standard deviation, SD) and rate of change of SNa+ (slope of SNa+) with the risk of all-cause death in incident HD patients. Methods: We studied 20,193 incident HD patients (age 63.3±15.0 years, 59% males, 34% diabetic, relative interdialytic weight gain (IDWG%) 2.9%±1.0%, BMI 26.9±7.5 kg/m2) from Europe (N=14,763) and the U.S. (N=5,430). During baseline (first 12 months on HD) mean SNa+, SNa+ slope and SNa+ SD were computed. Patient outcomes were noted in months 13 to 24 (follow-up). We investigated the joint effects of SNa+ and a) SNa+ variability and (b) SNa+ slopes, respectively, during baseline on probability of death during follow-up using logistic regression with smoothing spline ANOVA models. Models were adjusted for age, gender, diabetes, IDWG%, serum albumin, phosphorus and BMI. Results: Risk of death was lowest with SNa+ around 138 to 141 mEq/L and SNa+ SD of 0 to 2 mEq/L. Deviations from this region in any direction were associated with increased risk. The increase in mortality risk associated with higher SNa+ variability was steepest at SNa+ levels <135 mEq/L (Fig 1). Stable SNa+ conferred the lowest risk with SNa+ levels around 139 to 142 mEq/L (Fig 2). Mortality risk progressively increased outside of this domain. Of note, over the range of our data, SNa+ departures from this range carried a steeper risk increase than departures in SNa+ slope. Lastly, while patients with SNa+ >136 mEq/L realized their best survival probability with SNa+ slopes around zero, in patients with SNa+ <136 mEq/L more positive SNa+ slopes were always linked to better survival along the entire range of SNa+ slopes (Fig 2). View larger version: In this window In a new window Download as PowerPoint Slide
    Full-text · Article · May 2014 · Nephrology Dialysis Transplantation
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    ABSTRACT: Introduction and Aims: According to classical nephrology practice, pure microscopic hematuria [MH] in early life is not considered a serious problem and up to date diagnostic studies are not always carried out. Family urine studies to confirm or rule out a familial disease should always be carried out early and if positive, molecular genetics should be used to study the whole family and establish the underlying genetic defect. Methods: During the last 30 years we have searched systematically in a homogeneous population of 650,000 people for familial MH and some 120 such families are under study so far. Molecular genetic studies during the last 10 years have led to the correct genetic diagnosis in 57 such families with a) 28 heterozygous COL4A3/A4 mutations and TBMN, b) 23 CFHR5 and C3 nephritis and c) 6 families with Alport syndrome. Results: Our most striking finding refers to the COL4A3/A4 heterozygous mutations that turn out to be the commonest cause of familial MH and have been identified in 249 carriers in 30 families. Some of these families are very big indeed and two of these mutations, COL4A3-G1334E and COL4A3-G871C, are particularly common. Mutation COL4A3-G1334E was found in 15 families and it accounts for 174 patients. C3 nephritis with the CFHR5 Cypriot mutation appears to be the 2nd commonest cause of familial MH with 150 carriers in 23 families. Classical XLAS, COL4A5 Alport was identified in 3 families with 9 affected males and 8 female carriers, while ARAS was also present in 3 additional families affecting 8 patients. Of the 249 patients with COL4A3/A4 heterozygous mutations 33 have reached ESKD and of the 150 CFHR5 patients 21 have reached ESKD. Conclusions: Our results strengthen the great significance of the heterozygous COL4A3/A4 mutations, not really well understood until after 1996, less than 20 years ago. These mutations are common, lead to TBMN and are the commonest cause of familial MH. More importantly however, these mutations lead much later in life to proteinuria, hypertension, CRF and ESKD and long term care is mandatory with prompt attention to the addition of proteinuria that requires urgent treatment. Heterozygous mutations COL4A3/A4 cause twice more patients to reach ESKD compared to classical XLAS and ARAS but fortunately at a much older age. Molecular genetics should be used more widely for an early diagnosis of this entity and more renal attention should be given to these patients to preserve kidney function and avoid ESKD.
    Full-text · Article · May 2014 · Nephrology Dialysis Transplantation
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    ABSTRACT: Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.
    Preview · Article · Apr 2014 · Journal of the American Society of Nephrology

  • No preview · Article · Dec 2013 · Molecular Immunology

  • No preview · Article · Dec 2013 · Molecular Immunology
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    ABSTRACT: Atypical haemolytic uraemic syndrome (aHUS) is a severe renal disease caused by deregulation of the alternative complement pathway. The RCA (Regulators of Complement Activation) gene cluster contains several genes that have been implicated in the pathogenesis of aHUS, including Complement Factor H (CFH). The gene for CFH is in close proximity to the genes encoding the 5 Complement Factor H related proteins (CFHRs). These are thought to have arisen from several large genomic duplications and thus have a very high degree of sequence identity to CFH. This homology predisposes this area to gene conversions and genomic rearrangements through non-allelic homologous recombination (NAHR) and microhomology-mediated end joining (MMEJ). In a sporadic case of aHUS, using multiplex ligation-dependent probe amplification, we describe a de novo deletion in the RCA cluster. Sequencing the PCR product across the deletion identified the breakpoint, with a 6.3 kb deletion between CFH intron 20 and the 3′UTR of CFH. Immediately adjacent to the breakpoint was a 7-bp region of microhomology. This is predicted to result in a novel hybrid CFH/CFHR3 gene. Western blotting confirmed 2 distinct anti-fH species in the sera of the affected individual. Using specific monoclonal antibodies, the higher molecular weight band gave a signal in keeping with the predicted CFH/CFHR3 hybrid protein. In conclusion we describe a novel deletion which occurred through MMEJ in aHUS. This produced a CFH/CFHR3 hybrid protein predicted to have impaired cell surface complement regulation, predisposing to disease. This highlights the importance of undertaking copy number variation analysis when undertaking genetic screening of aHUS patients.
    No preview · Article · Dec 2013 · Molecular Immunology

Publication Stats

7k Citations
1,120.70 Total Impact Points


  • 1983-2015
    • Newcastle University
      • • Institute of Genetic Medicine
      • • Institute of Cellular Medicine
      Newcastle-on-Tyne, England, United Kingdom
  • 2007-2013
    • University of Newcastle
      Newcastle, New South Wales, Australia
    • Washington University in St. Louis
      • Division of Rheumatology
      Saint Louis, MO, United States
  • 1986-2011
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • • Department of Respiratory Medicine
      • • Department of Clinical Biochemistry
      Newcastle-on-Tyne, England, United Kingdom
  • 2010
    • Lund University
      Lund, Skåne, Sweden
  • 2008
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      • Service d’Immunologie Biologique
      Paris, Ile-de-France, France
  • 2006
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 2005
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2004
    • Cliniques Universitaires Saint-Luc
      • Division of General Internal Medicine
      Bruxelles, Brussels Capital Region, Belgium
  • 2003
    • Institute of Human Genetics
      Amadavad, Gujarāt, India
  • 2002
    • University College London
      • Department of Structural and Molecular Biology
      London, ENG, United Kingdom
  • 1998
    • Université catholique de Louvain
      Лувен-ла-Нев, Wallonia, Belgium
    • Newcastle University Medicine Malaysia
      Bharu, Johor, Malaysia