title: Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
abstract: 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 ɛ) 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.
authors.affiliation: Department of Genetics, Yale University School of Medicine, and Howard Hughes Medical Institute, New Haven, Connecticut, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemaire
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Wai Ho
authors.initials: WH
authors.lastname: Tang
authors.forename: Moglie
authors.initials: M
authors.lastname: Le Quintrec
authors.forename: Fadi
authors.initials: F
authors.lastname: Fakhouri
authors.forename: Sophie
authors.initials: S
authors.lastname: Taque
authors.forename: François
authors.initials: F
authors.lastname: Nobili
authors.forename: Frank
authors.initials: F
authors.lastname: Martinez
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ji
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Denis
authors.initials: D
authors.lastname: Morin
authors.forename: Georges
authors.initials: G
authors.lastname: Deschenes
authors.forename: Véronique
authors.initials: V
authors.lastname: Baudouin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Llanas
authors.forename: Laure
authors.initials: L
authors.lastname: Collard
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Majid
authors.forename: Eva
authors.initials: E
authors.lastname: Simkova
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclerc
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Marie Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: John
authors.initials: J
authors.lastname: Hwa
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics; D065766:Atypical Hemolytic Uremic Syndrome; D002648:Child; D002675:Child, Preschool; D019852:Diacylglycerol Kinase / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051436:Renal Insufficiency, Chronic; D013921:Thrombocytopenia / Q000235:genetics; D057049:Thrombotic Microangiopathies / Q000235:genetics
chemical_list: C526464:DGKE protein, human; D019852:Diacylglycerol Kinase
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