Phenotypic expansion of DGKE-associated diseases

Rik 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

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complement activation. The recent discovery of loss-of-functionmutations 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 homozygositymapping 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.

Original languageEnglish
Pages (from-to)1408-1414
Number of pages7
JournalJournal of the American Society of Nephrology
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 1 2014

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Complement Activation
Mutation
Diacylglycerol Kinase
Thrombotic Microangiopathies
Exome
Therapeutics
Complement C3
Renal Insufficiency
Phenotype
Atypical Hemolytic Uremic Syndrome
Serum
Clinical Studies

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

Westland, R., Bodria, M., Carrea, A., Lata, S., Scolari, F., Fremeaux-Bacchi, V., ... Sanna-Cherchi, S. (2014). Phenotypic expansion of DGKE-associated diseases. Journal of the American Society of Nephrology, 25(7), 1408-1414. https://doi.org/10.1681/ASN.2013080886

Phenotypic expansion of DGKE-associated diseases. / Westland, Rik; Bodria, Monica; Carrea, Alba; Lata, Sneh; Scolari, Francesco; Fremeaux-Bacchi, Veronique; D'Agati, Vivette D.; Lifton, Richard P.; Gharavi, Ali G.; Marco Ghiggeri, Gian; Sanna-Cherchi, Simone.

In: Journal of the American Society of Nephrology, Vol. 25, No. 7, 01.07.2014, p. 1408-1414.

Research output: Contribution to journalArticle

Westland, R, Bodria, M, Carrea, A, Lata, S, Scolari, F, Fremeaux-Bacchi, V, D'Agati, VD, Lifton, RP, Gharavi, AG, Marco Ghiggeri, G & Sanna-Cherchi, S 2014, 'Phenotypic expansion of DGKE-associated diseases', Journal of the American Society of Nephrology, vol. 25, no. 7, pp. 1408-1414. https://doi.org/10.1681/ASN.2013080886
Westland R, Bodria M, Carrea A, Lata S, Scolari F, Fremeaux-Bacchi V et al. Phenotypic expansion of DGKE-associated diseases. Journal of the American Society of Nephrology. 2014 Jul 1;25(7):1408-1414. https://doi.org/10.1681/ASN.2013080886
Westland, Rik ; Bodria, Monica ; Carrea, Alba ; Lata, Sneh ; Scolari, Francesco ; Fremeaux-Bacchi, Veronique ; D'Agati, Vivette D. ; Lifton, Richard P. ; Gharavi, Ali G. ; Marco Ghiggeri, Gian ; Sanna-Cherchi, Simone. / Phenotypic expansion of DGKE-associated diseases. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 7. pp. 1408-1414.
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