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https://www.readbyqxmd.com/read/27374918/the-expanding-phenotypic-spectra-of-kidney-diseases-insights-from-genetic-studies
#1
REVIEW
Marijn F Stokman, Kirsten Y Renkema, Rachel H Giles, Franz Schaefer, Nine V A M Knoers, Albertien M van Eerde
Next-generation sequencing (NGS) has led to the identification of previously unrecognized phenotypes associated with classic kidney disease genes. In addition to improving diagnostics for genetically heterogeneous diseases and enabling a faster rate of gene discovery, NGS has enabled an expansion and redefinition of nephrogenetic disease categories. Findings from these studies raise the question of whether disease diagnoses should be made on clinical grounds, on genetic evidence or a combination thereof. Here, we discuss the major kidney disease-associated genes and gene categories for which NGS has expanded the phenotypic spectrum...
August 2016: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27177491/defining-the-genetics-of-thrombotic-microangiopathies
#2
REVIEW
Paula Vieira-Martins, Carine El Sissy, Pauline Bordereau, Aurelia Gruber, Jeremie Rosain, Veronique Fremeaux-Bacchi
The spectrum of the thrombotic microangiopathies (TMA) encompasses a heterogeneous group of disorders with hereditary and acquired forms. Endothelial cell injury in the microvasculature is common to all TMAs, whatever the pathophysiological process. In this review we describe genetic mutations characteristic of certain TMAs and review their contributions to disease. Recent identification of novel pathologic mutations has been enabled by exome studies. The monogenic forms of TMA are more frequently caused by recessive alterations in von Willebrand factor cleaving protease ADAMST13, leading to congenital thrombotic thrombocytopenic purpura, or cobalamine C and DGKE genes, leading to an atypical hemolytic-uremic syndrome (aHUS)-like TMA...
April 2016: Transfusion and Apheresis Science
https://www.readbyqxmd.com/read/27146825/testing-the-activity-of-complement-convertases-in-serum-plasma-for-diagnosis-of-c4nef-mediated-c3-glomerulonephritis
#3
Anna M Blom, Fernando Corvillo, Michal Magda, Grzegorz Stasiłojć, Pilar Nozal, Miguel Ángel Pérez-Valdivia, Virginia Cabello-Chaves, Santiago Rodríguez de Córdoba, Margarita López-Trascasa, Marcin Okrój
Autoantibodies termed C3-nephritic factor (C3NeF), which stabilize convertases of the alternative complement pathway, often stimulate autoinflammatory diseases. However, knowledge about analogous autoantibodies acting on the classical pathway (C4NeF) is limited to a few reports, which indicate association with kidney dysfunction, systemic lupus erythematous, and infections. C4NeF may appear independently from C3NeF, but the lack of a routine diagnostic method predisposes C4NeF for being an underestimated player in autoinflammatory episodes...
July 2016: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/26887830/loss-of-diacylglycerol-kinase-epsilon-in-mice-causes-endothelial-distress-and-impairs-glomerular-cox-2-and-pge2-production
#4
Jili Zhu, Moumita Chaki, Dongmei Lu, Chongyu Ren, Shan-Shan Wang, Alysha Rauhauser, Binghua Li, Susan Zimmerman, Bokkyoo Jun, Yong Du, Komal Vadnagara, Hanquin Wang, Sarah Elhadi, Richard J Quigg, Matthew K Topham, Chandra Mohan, Fatih Ozaltin, Xin J Zhou, Denise K Marciano, Nicolas G Bazan, Massimo Attanasio
Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP...
May 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/26479051/-genetics-of-ahus-and-transplant-recurrence
#5
Elena Bresin
Hemolytic uremic syndrome (HUS) is a rare disease with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical HUS (aHUS). Studies over the past decade have shown that the risk of post-transplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes (CFH, CFI, C3, CFB) encoding circulating complement proteins and regulators, while patients with mutations in membrane cofactor protein (MCP) and diacylglycerol kinase ɛ (DGKE) generally show good transplant outcome...
2015: Giornale Italiano di Nefrologia: Organo Ufficiale Della Società Italiana di Nefrologia
https://www.readbyqxmd.com/read/25917558/genetics-hidden-intronic-mutations-in-dgke-are-causative-of-ahus
#6
COMMENT
Jessica K Edwards
No abstract text is available yet for this article.
June 2015: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/25854283/characterization-of-a-new-dgke-intronic-mutation-in-genetically-unsolved-cases-of-familial-atypical-hemolytic-uremic-syndrome
#7
Caterina Mele, Mathieu Lemaire, Paraskevas Iatropoulos, Rossella Piras, Elena Bresin, Serena Bettoni, David Bick, Daniel Helbling, Regan Veith, Elisabetta Valoti, Roberta Donadelli, Luisa Murer, Maria Neunhäuserer, Matteo Breno, Véronique Frémeaux-Bacchi, Richard Lifton, Giuseppe Remuzzi, Marina Noris
BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS...
June 5, 2015: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/25765799/-atypical-hus-caused-by-complement-related-abnormalities
#8
REVIEW
Yoko Yoshida, Masanori Matsumoto
Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The term aHUS was historically used to distinguish this disorder from Shiga-toxin producing Escherichia coli (STEC)-HUS. Many aHUS cases (approximately 70%) are reportedly caused by uncontrolled complement activation due to genetic mutations in the alternative pathway, including complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP), thrombomodulin (THBD), complement component C3 (C3), and complement factor B (CFB)...
February 2015: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/25655457/dgke-disruption-ditches-complement-and-drives-p38-signaling
#9
COMMENT
K Vinod Vijayan
No abstract text is available yet for this article.
February 5, 2015: Blood
https://www.readbyqxmd.com/read/25599621/podocyte-dysfunction-in-atypical-haemolytic-uraemic-syndrome
#10
REVIEW
Marina Noris, Caterina Mele, Giuseppe Remuzzi
Genetic or autoimmune defects that lead to dysregulation of the alternative pathway of complement have been associated with the development of atypical haemolytic uraemic syndrome (aHUS), which is characterized by thrombocytopenia, haemolytic anaemia and acute kidney injury. The relationship between aHUS, podocyte dysfunction and the resultant proteinuria has not been adequately investigated. However, the report of mutations in diacylglycerol kinase ε (DGKE) as a cause of recessive infantile aHUS characterized by proteinuria, highlighted podocyte dysfunction as a potential complication of aHUS...
April 2015: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/25498910/loss-of-dgk%C3%AE%C2%B5-induces-endothelial-cell-activation-and-death-independently-of-complement-activation
#11
Sarah Bruneau, Mélanie Néel, Lubka T Roumenina, Marie Frimat, Lætitia Laurent, Véronique Frémeaux-Bacchi, Fadi Fakhouri
Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of the complement cascade, led us to consider other pathophysiologic mechanisms for this disease. Here, we demonstrate that loss of DGKε expression/activity in EC induces an increase in ICAM-1 and tissue factor expression through the upregulation of p38-MAPK-mediated signals, thus highlighting a proinflammatory and prothrombotic phenotype of DGKε-deficient ECs...
February 5, 2015: Blood
https://www.readbyqxmd.com/read/25178427/inborn-errors-of-metabolism-in-the-biosynthesis-and-remodelling-of-phospholipids
#12
REVIEW
Saskia B Wortmann, Marc Espeel, Ligia Almeida, Annette Reimer, Dennis Bosboom, Frank Roels, Arjan P M de Brouwer, Ron A Wevers
Since the proposal to define a separate subgroup of inborn errors of metabolism involved in the biosynthesis and remodelling of phospholipids, sphingolipids and long chain fatty acids in 2013, this group is rapidly expanding. This review focuses on the disorders involved in the biosynthesis of phospholipids. Phospholipids are involved in uncountable cellular processes, e.g. as structural components of membranes, by taking part in vesicle and mitochondrial fusion and fission or signal transduction. Here we provide an overview on both pathophysiology and the extremely heterogeneous clinical presentations of the disorders reported so far (Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC defect, SERAC1), Barth syndrome (or TAZ defect, TAZ), congenital muscular dystrophy due to CHKB deficiency (CHKB)...
January 2015: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/24594571/-pathophysiology-of-atypical-hemolytic-uremic-syndrome-ten-years-of-progress-from-laboratory-to-patient
#13
REVIEW
Véronique Frémeaux-Bacchi
Hemolytic Uremic Syndrome (HUS) is characterized by the triad of hemolytic anemia, thrombocytopenia and acute renal failure. The most frequent form in children is caused by Shiga-toxin producing Escherichia coli. In absence of Shiga-toxin infection, the HUS is called atypical (aHUS). Some HUS are secondary to Streptococcus pneumonia or human immunodeficiency virus infection, cancer, anti-cancer drugs, or cyclosporine. During the last decade, aHUS has been demonstrated to be a disorder of complement alternative pathway regulation...
2013: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/24511134/phenotypic-expansion-of-dgke-associated-diseases
#14
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
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...
July 2014: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/23875923/early-infantile-onset-of-atypical-hemolytic-uremic-syndrome-is-caused-by-recessive-mutations-in-dgke
#15
COMMENT
J W Lee
No abstract text is available yet for this article.
October 2013: Clinical Genetics
https://www.readbyqxmd.com/read/23743117/complement-activation-in-diseases-presenting-with-thrombotic-microangiopathy
#16
REVIEW
Seppo Meri
The complement system contains a great deal of biological "energy". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes...
September 2013: European Journal of Internal Medicine
https://www.readbyqxmd.com/read/23629598/identification-of-hepatic-microvascular-adhesion-related-genes-of-human-colon-cancer-cells-using-random-homozygous-gene-perturbation
#17
COMPARATIVE STUDY
Joana Márquez, Manu Kohli, Beatriz Arteta, Shaojing Chang, Wu-Bo Li, Michael Goldblatt, Fernando Vidal-Vanaclocha
Random homozygous gene perturbation (RHGP), in combination with liver sinusoidal endothelial cell (LSEC) adhesion screening of clonal colon cancer cells with perturbed genes, was used to identify genes contributing to the hepatic microvascular adhesion of colon cancer cells. Plasmid vector encoding transactivator and gene search vector were transfected into HT-29 human colorectal cancer cells to create a HT-29 RHGP cell library; the adhesion of these library cells to primary cultured mouse LSEC significantly decreased in the presence of RSL1 ligand (inducer), indicating that most of the genes contributing to HT-29 adhesion to LSEC were altered...
November 2013: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/23619787/dgke-and-atypical-hus
#18
COMMENT
Susan E Quaggin
A new study reports that recessive loss-of-function mutations in the gene encoding diacylglycerol kinase ε result in atypical hemolytic-uremic syndrome. Notably, mutations in DGKE are not associated with activation of the complement pathway, the only other identified cause of this disorder so far, and have important implications for patient management.
May 2013: Nature Genetics
https://www.readbyqxmd.com/read/23542698/recessive-mutations-in-dgke-cause-atypical-hemolytic-uremic-syndrome
#19
Mathieu Lemaire, Véronique Frémeaux-Bacchi, Franz Schaefer, Murim Choi, Wai Ho Tang, Moglie Le Quintrec, Fadi Fakhouri, Sophie Taque, François Nobili, Frank Martinez, Weizhen Ji, John D Overton, Shrikant M Mane, Gudrun Nürnberg, Janine Altmüller, Holger Thiele, Denis Morin, Georges Deschenes, Véronique Baudouin, Brigitte Llanas, Laure Collard, Mohammed A Majid, Eva Simkova, Peter Nürnberg, Nathalie Rioux-Leclerc, Gilbert W Moeckel, Marie Claire Gubler, John Hwa, Chantal Loirat, Richard P Lifton
Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease...
May 2013: Nature Genetics
https://www.readbyqxmd.com/read/23274426/dgke-variants-cause-a-glomerular-microangiopathy-that-mimics-membranoproliferative-gn
#20
COMPARATIVE STUDY
Fatih Ozaltin, Binghua Li, Alysha Rauhauser, Sung-Wan An, Oguz Soylemezoglu, Ipek Isik Gonul, Ekim Z Taskiran, Tulin Ibsirlioglu, Emine Korkmaz, Yelda Bilginer, Ali Duzova, Seza Ozen, Rezan Topaloglu, Nesrin Besbas, Shazia Ashraf, Yong Du, Chaoying Liang, Phylip Chen, Dongmei Lu, Komal Vadnagara, Susan Arbuckle, Deborah Lewis, Benjamin Wakeland, Richard J Quigg, Richard F Ransom, Edward K Wakeland, Matthew K Topham, Nicolas G Bazan, Chandra Mohan, Friedhelm Hildebrandt, Aysin Bakkaloglu, Chou-Long Huang, Massimo Attanasio
Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN...
February 2013: Journal of the American Society of Nephrology: JASN
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