title: Phenotypic expansion of DGKE-associated diseases.
abstract: Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complement activation. The recent discovery of loss-of-function mutations in DGKE in patients with aHUS and normal complement levels challenged this observation. DGKE, encoding diacylglycerol kinase-ε, has not been implicated in the complement cascade but hypothetically leads to a prothrombotic state. The discovery of this novel mechanism has potential implications for the treatment of infants with aHUS, who are increasingly treated with complement blocking agents. In this study, we used homozygosity mapping and whole-exome sequencing to identify a novel truncating mutation in DGKE (p.K101X) in a consanguineous family with patients affected by thrombotic microangiopathy characterized by significant serum complement activation and consumption of the complement fraction C3. Aggressive plasma infusion therapy controlled systemic symptoms and prevented renal failure, suggesting that this treatment can significantly affect the natural history of this aggressive disease. Our study expands the clinical phenotypes associated with mutations in DGKE and challenges the benefits of complement blockade treatment in such patients. Mechanistic studies of DGKE and aHUS are, therefore, essential to the design of appropriate therapeutic strategies in patients with DGKE mutations.
authors: Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands;
authors: Rik
authors: R
authors: Westland
authors: Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini, Genoa, Italy; Department of Clinical Medicine, Nephrology, and Health Sciences, Unit of Nephrology, University of Parma, Parma, Italy;
authors: Monica
authors: M
authors: Bodria
authors: Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini, Genoa, Italy;
authors: Alba
authors: A
authors: Carrea
authors: Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York;
authors: Sneh
authors: S
authors: Lata
authors: Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia, Italy;
authors: Francesco
authors: F
authors: Scolari
authors: Department of Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France; Centre de Recherche des Cordeliers, Unité Mixte de Recherche en Santé 872, Paris, France;
authors: Veronique
authors: V
authors: Fremeaux-Bacchi
authors: Department of Pathology, Columbia University, New York, New York; and.
authors: Vivette D
authors: VD
authors: D'Agati
authors: Department of Genetics, Howard Hughes Medical Institute and Yale Center for Mendelian Genomics, Yale University, New Haven, Connecticut.
authors: Richard P
authors: RP
authors: Lifton
authors: Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York;
authors: Ali G
authors: AG
authors: Gharavi
authors: Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini, Genoa, Italy;
authors: Gian Marco
authors: GM
authors: Ghiggeri
authors: Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; ss2517@columbia.edu.
authors: Simone
authors: S
authors: Sanna-Cherchi
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome; D002675:Child, Preschool; D019852:Diacylglycerol Kinase / Q000235:genetics*; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype
chemical_list: C526464:DGKE protein, human; D019852:Diacylglycerol Kinase