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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.
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http://dx.doi.org/10.1681/ASN.2013080886 | DOI Listing |
Semin Immunol
March 2025
Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney, Australia; Brain and Mind Centre, The University of Sydney, Sydney, Australia; The University of Sydney, Faculty of Medicine and Health, School of Medical Sciences, Sydney, Australia. Electronic address:
MOG antibody-associated disease (MOGAD), an inflammatory demyelinating pathology, is typically associated with the clinical phenotypes acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or transverse myelitis (TM). The mainstay of diagnosis is detection of antibodies targeting oligodendrocyte-expressed MOG (MOG-IgG). MOG-IgG-mediated demyelination occurs via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), enhanced cognate T-cell CNS infiltration and activation, and oligodendrocyte cytoskeleton disruption, but the exact role of the immune system in MOGAD is still poorly understood.
View Article and Find Full Text PDFMult Scler
March 2025
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Background: The complement system has been suspected to play a role in multiple sclerosis (MS) due to presence of complement activation products in MS lesions.
Objective: We sought to understand whether variation in the complement component 4 (C4) gene is associated with MS.
Methods: Here we used next-generation sequencing and our novel bioinformatics tool, , to interrogate C4 copy number variation in MS.
Semin Nephrol
March 2025
Department of Medicine, Division of Nephrology, Stanford University, Stanford, CA, USA. Electronic address:
IgA nephropathy (IgAN) is the most prevalent primary glomerular disease and has been recognized to carry a poor prognosis. It is therefore critical to identify the patients that will progress to ESKD and start treatments early. The current gold standard for diagnosis remains kidney biopsy.
View Article and Find Full Text PDFBlood Adv
March 2025
National Institute of Health, Bethesda, Maryland, United States.
Immune aplastic anemia (iAA) frequently results in transfusion dependence for platelets and packed red blood cells (PRBC), increasing the risk for complications. The most common immune mediated cause for platelet transfusion refractoriness is due to alloimmunization with human leukocyte antigen (HLA) antibody (Ab) to non-self class I antigens (Ag). The clinical impact of the HLA alloimmunization has not been well studied in patients with iAA.
View Article and Find Full Text PDFTheranostics
March 2025
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310003, China.
Significant efforts and resources have been dedicated to developing CRISPR-Cas based point-of-care testing (POCT) and self-diagnosis methods for nucleic acid pathogens, aiming to complement the gold standard quantitative PCR tests, particularly in settings where centralized facilities, trained personnel, or resource-intensive equipment are unavailable. However, the reliance on stationary, high-cost readout machinery hinders their full deployment at the point of care. We aimed to develop a solid-phase invertase-labeled reporter (ILR) system that enables convenient readout of CRISPR-Cas reactions, facilitate HPV detection in a POCT-compatible manner.
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