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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome
Nature Genetics, Volume 45, No. 5, Year 2013
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Description
Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase É) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS. © 2013 Nature America, Inc. All rights reserved.
Authors & Co-Authors
Lemaire, Matthieu
United States, New Haven
Yale School of Medicine
Frémeaux-Bacchi, Véronique
France, Paris
Hôpital Européen Georges-pompidou
France, Paris
Centre de Recherche Des Cordeliers
Schaefer, Franz
Germany, Heidelberg
Universitätsklinikum Heidelberg
Choi, Murim
United States, New Haven
Yale School of Medicine
Tang, Waiho
United States, New Haven
Yale School of Medicine
Le Quintrec, Moglie
France, Paris
Centre de Recherche Des Cordeliers
Fakhouri, Fadi
France, Nantes
Chu de Nantes
Taque, Sophie
France, Rennes
Centre Hospitalier Universitaire de Rennes
Nobili, François
France, Besancon
Centre Hospitalier Universitaire de Besançon
Martínez, Frank Eduardo
France, Paris
Hôpital Necker Enfants Malades
Ji, Weizhen
United States, New Haven
Yale School of Medicine
Overton, John D.
United States, New Haven
Yale School of Medicine
Mane, Shrikant M.
United States, New Haven
Yale School of Medicine
Nürnberg, Gudrun
Germany, Koln
Medizinische Fakultät
Altmüller, Janine
Germany, Koln
Medizinische Fakultät
Thiele, Holger
Germany, Koln
Medizinische Fakultät
Morin, Denis
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Dêschenes, Georges
France, Paris
Hôpital Robert-debré Ap-hp
Baudouin, Véronique
France, Paris
Hôpital Robert-debré Ap-hp
Llanas, Brigitte
France, Talence
Centre Hospitalier Universitaire de Bordeaux
Collard, Laure
Belgium
Centre Hospitalier Chretien
Majid, Mohammad Abdul
United Arab Emirates, Dubai
Dubai Hospital
Šimková, Eva
United Arab Emirates, Dubai
Dubai Hospital
Nürnberg, Peter
Germany, Koln
Medizinische Fakultät
Germany, Koln
Universität zu Köln
Germany, Berlin
Atlas Biolabs Gmbh
Rioux-Leclerc, Nathalie
France, Rennes
Centre Hospitalier Universitaire de Rennes
Moeckel, Gilbert W.
United States, New Haven
Yale School of Medicine
Gübler, Marie Claire
France, Paris
Hôpital Necker Enfants Malades
Hwa, John
United States, New Haven
Yale School of Medicine
Loirat, Chantal
France, Paris
Hôpital Robert-debré Ap-hp
Lifton, Richard P.
United States, New Haven
Yale School of Medicine
Statistics
Citations: 426
Authors: 30
Affiliations: 16
Identifiers
Doi:
10.1038/ng.2590
ISSN:
10614036
e-ISSN:
15461718
Research Areas
Genetics And Genomics
Noncommunicable Diseases