Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Mathieu Lemaire; Véronique Frémeaux-Bacchi; Franz Schaefer; Murim Choi; Wai Ho Tang; Moglie Le Quintrec; Fadi Fakhouri; Sophie Taque; François Nobili; Frank Martinez; Weizhen Ji; John D. Overton; Shrikant M. Mane; Gudrun Nürnberg; Janine Altmüller; Holger Thiele; Denis Morin; Georges Deschenes; Véronique Baudouin; Brigitte Llanas; Laure Collard; Mohammed A. Majid; Eva Simkova; Peter Nürnberg; Nathalie Rioux-Leclerc; Gilbert W. Moeckel; Marie Claire Gubler; John Hwa; Chantal Loirat; Richard P. Lifton

doi:10.1038/ng.2590

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Mathieu Lemaire, Véronique Frémeaux-Bacchi, Franz Schaefer, Murim Choi, Wai Ho Tang, Moglie Le Quintrec, Fadi Fakhouri, Sophie Taque, François Nobili, Frank Martinez, Weizhen Ji, John D. Overton, Shrikant M. Mane, Gudrun Nürnberg, Janine Altmüller, Holger Thiele, Denis Morin, Georges Deschenes, Véronique Baudouin, Brigitte LlanasLaure Collard, Mohammed A. Majid, Eva Simkova, Peter Nürnberg, Nathalie Rioux-Leclerc, Gilbert W. Moeckel, Marie Claire Gubler, John Hwa, Chantal Loirat, Richard P. Lifton

Research output: Contribution to journal › Article › peer-review

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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 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.

Original language	English
Pages (from-to)	531-536
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	5
DOIs	https://doi.org/10.1038/ng.2590
Publication status	Published - May 2013
Externally published	Yes

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Lemaire, M., Frémeaux-Bacchi, V., Schaefer, F., Choi, M., Tang, W. H., Quintrec, M. L., Fakhouri, F., Taque, S., Nobili, F., Martinez, F., Ji, W., Overton, J. D., Mane, S. M., Nürnberg, G., Altmüller, J., Thiele, H., Morin, D., Deschenes, G., Baudouin, V., ... Lifton, R. P. (2013). Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics, 45(5), 531-536. https://doi.org/10.1038/ng.2590

@article{cd00030d21a54516b73d9c526051ad56,

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 {\'E}) 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.",

author = "Mathieu Lemaire and V{\'e}ronique Fr{\'e}meaux-Bacchi and Franz Schaefer and Murim Choi and Tang, {Wai Ho} and Quintrec, {Moglie Le} and Fadi Fakhouri and Sophie Taque and Fran{\c c}ois Nobili and Frank Martinez and Weizhen Ji and Overton, {John D.} and Mane, {Shrikant M.} and Gudrun N{\"u}rnberg and Janine Altm{\"u}ller and Holger Thiele and Denis Morin and Georges Deschenes and V{\'e}ronique Baudouin and Brigitte Llanas and Laure Collard and Majid, {Mohammed A.} and Eva Simkova and Peter N{\"u}rnberg and Nathalie Rioux-Leclerc and Moeckel, {Gilbert W.} and Gubler, {Marie Claire} and John Hwa and Chantal Loirat and Lifton, {Richard P.}",

note = "Funding Information: We thank the subjects with aHUS, their families and the health care professionals whose participation made this study possible; J. Zhang, C. Nelson-Williams, S. Mentone, D. Beury and other members of the complement laboratory at H{\^o}pital Europ{\'e}en Georges-Pompidou for technical support; the staff of the Yale Center for Genome Analysis for exome sequencing; S. Ishibe, S. Shibata, U. Scholl, M.-A. Dragon-Durey, L. Roumenina, M. Malina, Q. Vincent and L. Abel for helpful discussions; and D. Damotte (Assistance Publique-H{\^o}pitaux de Paris, H{\^o}pital H{\^o}tel-Dieu, Service d{\textquoteright}Anatomie Pathologique) for the anti-CD34 staining. This work was supported by US National Institutes of Health (NIH) grants U54 HG006504 01 (Yale Center for Mendelian Genomics), P30 DK079310 05 (Yale O{\textquoteright}Brien Center for Kidney Research) and UL1TR00142 07 (Yale Center for Translational Science Award), grants from the D{\'e}l{\'e}gation R{\'e}gionale {\`a} la Recherche Clinique, Assistance Publique–H{\^o}pitaux de Paris to V.F.-B., such as Programme Hospitalier de Recherche Clinique (AOM08198) and the Association pour l{\textquoteright}Information et la Recherche dans les maladies R{\'e}nales g{\'e}n{\'e}tiques (AIRG France), and a European Community FP7 Grant 2012-305608 (EURenOmics) to F.S. and V.F.-B. M.L. is the recipient of a Kidney Research Scientist Core Education and National Training (KRESCENT) Program Post-Doctoral Fellowship Award from the Kidney Foundation of Canada and is a member of the Investigative Medicine PhD program at Yale University School of Medicine.",

year = "2013",

month = may,

doi = "10.1038/ng.2590",

language = "English",

volume = "45",

pages = "531--536",

number = "5",

}

Lemaire, M, Frémeaux-Bacchi, V, Schaefer, F, Choi, M, Tang, WH, Quintrec, ML, 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, MC, Hwa, J, Loirat, C & Lifton, RP 2013, 'Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome', Nature Genetics, vol. 45, no. 5, pp. 531-536. https://doi.org/10.1038/ng.2590

TY - JOUR

T1 - Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

AU - Lemaire, Mathieu

AU - Frémeaux-Bacchi, Véronique

AU - Schaefer, Franz

AU - Choi, Murim

AU - Tang, Wai Ho

AU - Quintrec, Moglie Le

AU - Fakhouri, Fadi

AU - Taque, Sophie

AU - Nobili, François

AU - Martinez, Frank

AU - Ji, Weizhen

AU - Overton, John D.

AU - Mane, Shrikant M.

AU - Nürnberg, Gudrun

AU - Altmüller, Janine

AU - Thiele, Holger

AU - Morin, Denis

AU - Deschenes, Georges

AU - Baudouin, Véronique

AU - Llanas, Brigitte

AU - Collard, Laure

AU - Majid, Mohammed A.

AU - Simkova, Eva

AU - Nürnberg, Peter

AU - Rioux-Leclerc, Nathalie

AU - Moeckel, Gilbert W.

AU - Gubler, Marie Claire

AU - Hwa, John

AU - Loirat, Chantal

AU - Lifton, Richard P.

N1 - Funding Information: We thank the subjects with aHUS, their families and the health care professionals whose participation made this study possible; J. Zhang, C. Nelson-Williams, S. Mentone, D. Beury and other members of the complement laboratory at Hôpital Européen Georges-Pompidou for technical support; the staff of the Yale Center for Genome Analysis for exome sequencing; S. Ishibe, S. Shibata, U. Scholl, M.-A. Dragon-Durey, L. Roumenina, M. Malina, Q. Vincent and L. Abel for helpful discussions; and D. Damotte (Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Service d’Anatomie Pathologique) for the anti-CD34 staining. This work was supported by US National Institutes of Health (NIH) grants U54 HG006504 01 (Yale Center for Mendelian Genomics), P30 DK079310 05 (Yale O’Brien Center for Kidney Research) and UL1TR00142 07 (Yale Center for Translational Science Award), grants from the Délégation Régionale à la Recherche Clinique, Assistance Publique–Hôpitaux de Paris to V.F.-B., such as Programme Hospitalier de Recherche Clinique (AOM08198) and the Association pour l’Information et la Recherche dans les maladies Rénales génétiques (AIRG France), and a European Community FP7 Grant 2012-305608 (EURenOmics) to F.S. and V.F.-B. M.L. is the recipient of a Kidney Research Scientist Core Education and National Training (KRESCENT) Program Post-Doctoral Fellowship Award from the Kidney Foundation of Canada and is a member of the Investigative Medicine PhD program at Yale University School of Medicine.

PY - 2013/5

Y1 - 2013/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84878608990&partnerID=8YFLogxK

U2 - 10.1038/ng.2590

DO - 10.1038/ng.2590

M3 - Article

C2 - 23542698

AN - SCOPUS:84878608990

SN - 1061-4036

VL - 45

SP - 531

EP - 536

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

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