Phenotypic expansion of DGKE-associated diseases.

TitlePhenotypic expansion of DGKE-associated diseases.
Publication TypeJournal Article
Year of Publication2014
AuthorsWestland, R, Bodria, M, Carrea, A, Lata, S, Scolari, F, Fremeaux-Bacchi, V, D'Agati, VD, Lifton, RP, Gharavi, AG, Ghiggeri, GMarco, Sanna-Cherchi, S
JournalJ Am Soc Nephrol
Date Published2014 Jul
KeywordsAtypical Hemolytic Uremic Syndrome, Child, Preschool, Diacylglycerol Kinase, Female, Hemolytic-Uremic Syndrome, Humans, Male, Pedigree, Phenotype

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.

Alternate JournalJ. Am. Soc. Nephrol.
PubMed ID24511134
PubMed Central IDPMC4073436
Grant ListP30 DK079310 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
HG006504 / HG / NHGRI NIH HHS / United States