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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2014 ; 25
(7
): 1408-14
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Phenotypic expansion of DGKE-associated diseases
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Westland R
; Bodria M
; Carrea A
; Lata S
; Scolari F
; Fremeaux-Bacchi V
; D'Agati VD
; Lifton RP
; Gharavi AG
; Ghiggeri GM
; Sanna-Cherchi S
J Am Soc Nephrol
2014[Jul]; 25
(7
): 1408-14
PMID24511134
show ga
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-?, 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.
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