Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

• Published in: Nature genetics Vol. 45; no. 5; pp. 531 - 536
• Main Authors: Lemaire, Mathieu, Frémeaux-Bacchi, Véronique, Schaefer, Franz, Choi, Murim, Tang, Wai Ho, Le Quintrec, Moglie, Fakhouri, Fadi, Taque, Sophie, Nobili, François, Martinez, Frank, Ji, Weizhen, Overton, John D, Mane, Shrikant M, Nürnberg, Gudrun, Altmüller, Janine, Thiele, Holger, Morin, Denis, Deschenes, Georges, Baudouin, Véronique, Llanas, Brigitte, Collard, Laure, Majid, Mohammed A, Simkova, Eva, Nürnberg, Peter, Rioux-Leclerc, Nathalie, Moeckel, Gilbert W, Gubler, Marie Claire, Hwa, John, Loirat, Chantal, Lifton, Richard P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2013; Nature Publishing Group
• Subjects: 631/208/212; 631/208/2489/144; 692/308/2056; 692/699/1585/2159; 692/699/1585/2159/1545; 692/699/1585/2759; Acute Kidney Injury - genetics; Age; Agriculture; Amino acids; Animal Genetics and Genomics; Atypical Hemolytic Uremic Syndrome; Biomedicine; Cancer Research; Care and treatment; Child; Child, Preschool; Confidence intervals; Diacylglycerol Kinase - genetics; Exome - genetics; Female; Gene Function; Gene mutations; Genealogy; Genes, Recessive - genetics; Genetic aspects; Genetics; Genomes; Health aspects; Hemolytic-uremic syndrome; Hemolytic-Uremic Syndrome - etiology; Hemolytic-Uremic Syndrome - pathology; Human Genetics; Humans; Hypertension; Immunoenzyme Techniques; Infant; Kidneys; letter; Life Sciences; Male; Molecular Sequence Data; Mutation; Mutation - genetics; Pediatrics; Proteins; Renal Insufficiency, Chronic; Risk factors; Siblings; Studies; Thrombocytopenia - genetics; Thromboembolism; Thrombotic Microangiopathies - genetics; Von Willebrand factor; Germany; Thrombocytopenia; Hemolytic-Uremic Syndrome; Acute Kidney Injury; Genes; Humans; Preschool; Molecular Sequence Data; Infant; Male; Thrombotic Microangiopathies; Recessive; Immunoenzyme Techniques; Diacylglycerol Kinase; Exome; Chronic; Renal Insufficiency; Female; Mutation; Child
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2590

Richard Lifton, Véronique Frémeaux-Bacchi and colleagues report that recessive mutations in
DGKE
cause atypical hemolytic-uremic syndrome with an early age of onset progressing to chronic kidney disease. The authors propose that loss of DGKE results in a prothrombotic state that underlies disease pathogenesis.
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
1
. Atypical HUS (aHUS) can result from genetic or autoimmune factors
2
that lead to pathologic complement cascade activation
3
. 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.