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      Whole-exome sequencing of a patient with severe and complex hemostatic abnormalities reveals a possible contributing frameshift mutation in C3AR1

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          Abstract

          The increasing availability of genome-wide analysis has made it possible to rapidly sequence the exome of patients with undiagnosed or unresolved medical conditions. Here, we present the case of a 64-yr-old male patient with schistocytes in the peripheral blood smear and a complex and life-threatening coagulation disorder causing recurrent venous thromboembolic events, severe thrombocytopenia, and subdural hematomas. Whole-exome sequencing revealed a frameshift mutation ( C3AR1 c.355-356dup, p.Asp119Alafs*19) resulting in a premature stop codon in C3AR1 (Complement Component 3a Receptor 1). Based on this finding, atypical hemolytic uremic syndrome was suspected because of a genetic predisposition, and a targeted treatment regime with eculizumab was initiated. Life-threatening hemostatic abnormalities would most likely have persisted had it not been for the implementation of whole-exome sequencing in this particular clinical setting.

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          Atypical hemolytic-uremic syndrome.

          Marina Noris, Giuseppe Remuzzi (2009)
          Article 0 comments Cited 337 times – based on 0 reviews     Review now
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            Complement-targeted therapeutics.

            Daniel Ricklin, John D Lambris (2007)
            The complement system is a central component of innate immunity and bridges the innate to the adaptive immune response. However, it can also turn its destructive capabilities against host cells and is involved in numerous diseases and pathological conditions. Modulation of the complement system has been recognized as a promising strategy in drug discovery, and a large number of therapeutic modalities have been developed. However, successful marketing of complement-targeted drugs has proved to be more difficult than initially expected, and many strategies have been discontinued. The US Food and Drug Administration's approval of the first complement-specific drug, an antibody against complement component C5 (eculizumab; Soliris), in March 2007, was a long-awaited breakthrough in the field. Approval of eculizumab validates the complement system as therapeutic target and might facilitate clinical development of other promising drug candidates.
            Article 0 comments Cited 134 times – based on 0 reviews     Review now
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              Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32.

              Jorge Esparza-Gordillo, Elena Goicoechea de Jorge, Alfonso Buil … (2005)
              The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cold Spring Harb Mol Case Stud
                Journal ID (iso-abbrev): Cold Spring Harb Mol Case Stud
                Journal ID (hwp): cshmcs
                Journal ID (pmc): cshmcs
                Journal ID (publisher-id): cshmcs
                Title: Cold Spring Harbor Molecular Case Studies
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 2373-2865
                ISSN (Electronic): 2373-2873
                Publication date (Print): July 2016
                Volume: 2
                Issue: 4
                Electronic Location Identifier: a000828
                Affiliations
                [1 ]Department of Hematology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark;
                [2 ]Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
                Author notes
                Article
                Publisher ID: LeinoeMCS000828
                DOI: 10.1101/mcs.a000828
                PMC ID: 4990812
                PubMed ID: 27551680
                SO-VID: 8dcc4b43-3086-4c48-8449-495236240cda
                Copyright © © 2016 Leinøe et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

                History
                Date received : 6 December 2015
                Date accepted : 7 April 2016
                Page count
                Pages: 9
                Categories
                Subject: Research Report

                Keywords: acute disseminated intravascular coagulation,recurrent deep vein thrombosis
                Data availability:
                Keywords: acute disseminated intravascular coagulation, recurrent deep vein thrombosis

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