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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.
AuthorsRik Westland, Monica Bodria, Alba Carrea, Sneh Lata, Francesco Scolari, Veronique Fremeaux-Bacchi, Vivette D D'Agati, Richard P Lifton, Ali G Gharavi, Gian Marco Ghiggeri, Simone Sanna-Cherchi
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 7 Pg. 1408-14 (Jul 2014) ISSN: 1533-3450 [Electronic] United States
PMID24511134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 by the American Society of Nephrology.
Chemical References
  • DGKE protein, human
  • Diacylglycerol Kinase
Topics
  • Atypical Hemolytic Uremic Syndrome
  • Child, Preschool
  • Diacylglycerol Kinase (genetics)
  • Female
  • Hemolytic-Uremic Syndrome (genetics)
  • Humans
  • Male
  • Pedigree
  • Phenotype

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