Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.

TitleRecessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
Publication TypeJournal Article
Year of Publication2013
AuthorsLemaire, M, Fremeaux-Bacchi, V, Schaefer, F, Choi, M, Tang, WHo, Le Quintrec, M, Fakhouri, F, Taque, S, Nobili, F, Martinez, F, Ji, W, Overton, JD, Mane, SM, Nürnberg, G, Altmüller, J, Thiele, H, Morin, D, Deschenes, G, Baudouin, V, Llanas, B, Collard, L, Majid, MA, Simkova, E, Nürnberg, P, Rioux-Leclerc, N, Moeckel, GW, Gubler, MClaire, Hwa, J, Loirat, C, Lifton, RP
JournalNat Genet
Date Published2013 May
KeywordsAcute Kidney Injury, Atypical Hemolytic Uremic Syndrome, Child, Child, Preschool, Diacylglycerol Kinase, Exome, Female, Genes, Recessive, Hemolytic-Uremic Syndrome, Humans, Immunoenzyme Techniques, Infant, Male, Molecular Sequence Data, Mutation, Renal Insufficiency, Chronic, Thrombocytopenia, Thrombotic Microangiopathies

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.

Alternate JournalNat. Genet.
PubMed ID23542698
PubMed Central IDPMC3719402
Grant ListR01 HL115247 / HL / NHLBI NIH HHS / United States
UL1TR00142 07 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
U54 HG006504 01 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
UL1 TR000142 / TR / NCATS NIH HHS / United States
P30 DK079310 05 / DK / NIDDK NIH HHS / United States