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      Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

      research-article
      1 , 2 , 3 , 4 , 5 , 4 , 6 , 7 , 8 , 5 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 15 , 1 , 15 , 1 , 2 , 1 , 2 ,
      Kidney International
      Elsevier
      atypical hemolytic uremic syndrome, diacylglycerol kinase ε, membranoproliferative glomerulonephritis, thrombotic microangiopathy

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          Abstract

          Recessive mutations in diacylglycerol kinase epsilon ( DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

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          Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30 min and 2 h after submission.
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            Pfam: the protein families database

            Pfam, available via servers in the UK (http://pfam.sanger.ac.uk/) and the USA (http://pfam.janelia.org/), is a widely used database of protein families, containing 14 831 manually curated entries in the current release, version 27.0. Since the last update article 2 years ago, we have generated 1182 new families and maintained sequence coverage of the UniProt Knowledgebase (UniProtKB) at nearly 80%, despite a 50% increase in the size of the underlying sequence database. Since our 2012 article describing Pfam, we have also undertaken a comprehensive review of the features that are provided by Pfam over and above the basic family data. For each feature, we determined the relevance, computational burden, usage statistics and the functionality of the feature in a website context. As a consequence of this review, we have removed some features, enhanced others and developed new ones to meet the changing demands of computational biology. Here, we describe the changes to Pfam content. Notably, we now provide family alignments based on four different representative proteome sequence data sets and a new interactive DNA search interface. We also discuss the mapping between Pfam and known 3D structures.
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              20 years of the SMART protein domain annotation resource

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                Author and article information

                Contributors
                Journal
                Kidney Int
                Kidney Int
                Kidney International
                Elsevier
                0085-2538
                1523-1755
                1 June 2020
                June 2020
                : 97
                : 6
                : 1260-1274
                Affiliations
                [1 ]National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
                [2 ]Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
                [3 ]Division of Paediatric Nephrology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
                [4 ]Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
                [5 ]Division of Pediatric Nephrology, University of Miami, Miami, Florida, USA
                [6 ]Department of General Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
                [7 ]Children’s Renal and Urology Unit, Nottingham Children’s Hospital, Nottingham University Hospitals NHS Foundation Trust, Nottingham, UK
                [8 ]Leeds Teaching Hospitals NHS Trust, Leeds, UK
                [9 ]Department of Renal Medicine, University College London, UK
                [10 ]Department of Paediatric Nephrology, Bristol Royal Hospital For Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
                [11 ]Department of Paediatric Nephrology, Alder Hey Children’s Hospital NHS Trust, Liverpool, UK
                [12 ]Department of Paediatric Nephrology, Starship Children’s Hospital, Grafton, Auckland, New Zealand
                [13 ]Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
                [14 ]Centre for Nephrology, Royal Free Hospital, University College London, London, UK
                [15 ]Great North Children’s Hospital, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle, UK
                Author notes
                [] Correspondence: David Kavanagh, National Renal Complement Therapeutics Centre, Atypical Haemolytic Uremic Syndrome Service, Building 26, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. david.kavanagh@ 123456newcastle.ac.uk
                Article
                S0085-2538(20)30226-X
                10.1016/j.kint.2020.01.045
                7242908
                32386968
                31f80e3d-2313-4b64-991d-49d49f99e472
                © 2020 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 November 2019
                : 15 January 2020
                : 31 January 2020
                Categories
                Article

                Nephrology
                atypical hemolytic uremic syndrome,diacylglycerol kinase ε,membranoproliferative glomerulonephritis,thrombotic microangiopathy

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