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Olivia Boyer Stéphanie Woerner Fan Yang Edward J. Oakeley Bolan Linghu Olivier Gribouval Marie-Josèphe Tête José S. Duca Lloyd Klickstein Amy J. Damask Joseph D. Szustakowski Fran?oise Heibel Marie Matignon Véronique Baudouin Fran?ois Chantrel Jacqueline Champigneulle Laurent Martin Patrick Nitschké Marie-Claire Gubler Keith J. Johnson Salah-Dine Chibout Corinne Antignac 《Journal of the American Society of Nephrology : JASN》2013,24(8):1216-1222
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Shazia Adalat Adrian S. Woolf Karen A. Johnstone Andrea Wirsing Lorna W. Harries David A. Long Raoul C. Hennekam Sarah E. Ledermann Lesley Rees William van't Hoff Stephen D. Marks Richard S. Trompeter Kjell Tullus Paul J. Winyard Janette Cansick Imran Mushtaq Harjeeta K. Dhillon Coralie Bingham Emma L. Edghill Rukshana Shroff Horia Stanescu Gerhart U. Ryffel Sian Ellard Detlef Bockenhauer 《Journal of the American Society of Nephrology : JASN》2009,20(5):1123-1131
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Rasheed A. Gbadegesin Gentzon Hall Adebowale Adeyemo Nils Hanke Irini Tossidou James Burchette Guanghong Wu Alison Homstad Matthew A. Sparks Jose Gomez Ruiji Jiang Andrea Alonso Peter Lavin Peter Conlon Ron Korstanje M. Christine Stander Ghaidan Shamsan Moumita Barua Robert Spurney Pravin C. Singhal Jeffrey B. Kopp Hermann Haller David Howell Martin R. Pollak Andrey S. Shaw Mario Schiffer Michelle P. Winn 《Journal of the American Society of Nephrology : JASN》2014,25(9):1991-2002
FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1–associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragm–associated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.FSGS is a clinicopathologic entity that is characterized by nephrotic syndrome (NS), focally sclerotic glomeruli, and effacement of podocyte foot processes and is a common cause of ESRD.1 The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided evidence that disruption of podocyte structure and function is central to its pathogenesis. The highly specialized apparatus of the glomerular filtration barrier (GFB) is composed of the podocyte and slit diaphragm, the glomerular basement membrane, and specialized fenestrated endothelium. The podocyte and slit diaphragm play a central role in maintaining the structural and functional integrity of the GFB. This is evidenced by the number of genetic mutations found in familial FSGS and NS; many of these gene products contribute to signaling at the podocyte slit diaphragm or localize to the podocyte cytoskeleton.2–8 However, the entire repertoire of genes and proteins that are important in maintaining the functional integrity of the GFB remains unknown. It is estimated that >90% of the genetic causes of hereditary FSGS and NS remain unknown9; thus, the study of large kindreds remains an invaluable tool for unraveling the complexity of the molecular interactions that are responsible for maintaining the integrity of the podocyte and GFB.We identified a pedigree from the United States with autosomal dominant (AD) FSGS. Linkage analysis was carried out and we obtained suggestive multipoint logarithm of odds (LOD) scores of 1.7, 1.7, and 1.8 on chromosomes 2p, 5p, and 7p respectively. Whole-exome sequencing identified a deleterious heterozygous mutation R431C in ANLN, the gene encoding the F-actin binding protein anillin. We found another variant G618C that segregates with disease in a second family with FSGS. Anillin is important in cytokinesis and it interacts with key proteins such as CD2AP and mDia2 during cell division.10–13 In addition, it regulates cell growth by its interaction with the promigratory and prosurvival phosphoinositide 3 kinase/AKT (protein kinase B) pathway.10–13 Overexpression of the mutant anillin in immortalized human podocytes causes increased podocyte motility compared with wild-type overexpression. In contrast with intact anillin, the mutant displays a significantly reduced binding affinity to CD2AP. These findings reemphasize the importance of podocyte cell integrity, cell survival pathways, and cell migration in the pathogenesis of FSGS. 相似文献
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PAX2 mutations in oligomeganephronia 总被引:7,自引:0,他引:7
Salomon R Tellier AL Attie-Bitach T Amiel J Vekemans M Lyonnet S Dureau P Niaudet P Gubler MC Broyer M 《Kidney international》2001,59(2):457-462
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Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland 下载免费PDF全文
Unnur Styrkarsdottir Gudmar Thorleifsson Berglind Eiriksdottir Sigurjon A Gudjonsson Thorvaldur Ingvarsson Jacqueline R Center Tuan V Nguyen John A Eisman Claus Christiansen Unnur Thorsteinsdottir Gunnar Sigurdsson Kari Stefansson 《Journal of bone and mineral research》2016,31(1):173-179
We conducted a genome‐wide association study of low bone mineral density (BMD) at the hip and spine utilizing sequence variants found through whole‐genome sequencing of 2636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause the autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low BMD and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (p = 1.8 × 10?7, odds ratio [OR] = 4.61 [95% confidence interval (CI) 2.59, 8.18]), whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (p = 1.9 × 10?8, OR = 9.34 [95% CI 4.28, 20.3]). Association with fractures was p = 2.2 × 10?5, OR = 3.75 (95% CI 2.03, 6.93) and p = 0.0023, OR = 4.32 (95% CI 1.69, 11.1), respectively. The carriers of these variants do not have signs of osteogenesis imperfecta other than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. © 2015 American Society for Bone and Mineral Research. 相似文献
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Fogo AB Alpers CE D'Agati VD 《Kidney international》2011,80(3):319; author reply 319-319; author reply 320
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《Renal failure》2013,35(3):231-236
Idiopathic nephrotic syndrome (NS) associated with focal segmental glomerulosclerosis (FSGS) and severe renal function impairment is usually refractory to the conventional treatment and progresses to end‐stage renal disease. Herein, we reported 10 patients with NS‐FSGS who had initially had CCr 34 ± 12 mL/min/1.73m2 (normal 120 mL/min/1.73m2), FE Mg 7.8 ± 2.6% (normal 2.2%), 24‐h urinary protein 3.1 g (normal < 200 mg) and been followed up for over 10 years. The initial intrarenal hemodynamic study revealed a marked elevation of efferent arteriolar resistance (RE 17289 ± 8636 dyne.s.cm? 5; normal 3000 dyne.s.cm? 5), intraglomerular hypertension (PG 57 ± 1 mm Hg; normal 52 mm Hg), hyperfiltration (FF 0.24; normal 0.2), marked reductions in GFR 35 ± 17 mL/min/1.73m2, renal plasma flow (RPF 159 ± 61 mL/min/1.73m2; normal 600 mL/min/1.73m2) and peritubular capillary flow (PTCF 123 ± 57 mL/min/1.73m2; normal 480 mL/min/1.73m2). Such a hemodynamic alteration indicated a hemodynamic maladjustment with a preferential constriction at RE. Treatment consists of multidrugs, namely angiotensin converting enzyme inhibitor, calcium channel blocker, antiplatelet and anticoagulant, with or without angiotensin II receptor antagonist. Following the treatment, correction of hemodynamic maladjustment has been achieved which is characterized by reductions in RE 6046 ± 2191 dyne.s.cm? 5, PG 52 ± mm Hg, FF 0.19 ± 0.1 and increments in RPF 341 ± 118 mL/min/1.73m2, PTCF 280 ± 106 mL/min/1.73m2 and GFR 64 ± 17 mL/min/1.73m2. Coinciding with hemodynamic improvement, there has been a steadily increased creatinine clearance and improvement in FE Mg 4.3 ± 2.6% and suppression of proteinuria 0.29 ± 0.4g/24 h after the period of follow‐up of greater than 10 years. 相似文献
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Idiopathic nephrotic syndrome (NS) associated with focal segmental glomerulosclerosis (FSGS) and severe renal function impairment is usually refractory to the conventional treatment and progresses to end-stage renal disease. Herein, we reported 10 patients with NS-FSGS who had initially had CCr 34 +/- 12 mL/min/1.73 m2 (normal 120 mL/min/1.73 m2), FE Mg 7.8 +/- 2.6% (normal 2.2%), 24-h urinary protein 3.1 g (normal <200 mg) and been followed up for over 10 years. The initial intrarenal hemodynamic study revealed a marked elevation of efferent arteriolar resistance (RE 17289 +/- 8636 dyne x s x cm(-5); normal 3000 dyne x s x cm(-5)), intraglomerular hypertension (PG 57 +/- 1 mm Hg; normal 52 mm Hg), hyperfiltration (FF 0.24; normal 0.2), marked reductions in GFR 35 +/- 17 mL/min/1.73 m2, renal plasma flow (RPF 159 +/- 61 mL/min/1.73 m2; normal 600 mL/min/1.73 m2) and peritubular capillary flow (PTCF 123 +/- 57 mL/min/1.73 m2; normal 480 mL/min/1.73 m2). Such a hemodynamic alteration indicated a hemodynamic maladjustment with a preferential constriction at RE. Treatment consists of multidrugs, namely angiotensin converting enzyme inhibitor, calcium channel blocker, antiplatelet and anticoagulant, with or without angiotensin II receptor antagonist. Following the treatment, correction of hemodynamic maladjustment has been achieved which is characterized by reductions in RE 6046 +/- 2191 dyne x s x cm(-5), PG 52 +/- mm Hg, FF 0.19 +/- 0.1 and increments in RPF 341 +/- 118 mL/min/1.73 m2, PTCF 280 +/- 106 mL/min/1.73 m2 and GFR 64 +/- 17 mL/min/1.73 m2. Coinciding with hemodynamic improvement, there has been a steadily increased creatinine clearance and improvement in FE Mg 4.3 +/- 2.6% and suppression of proteinuria 0.29 +/- 0.4 g/24 h after the period of follow-up of greater than 10 years. 相似文献
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Human PAX2 mutations have been associated with abnormalities in the developing and adult kidney ranging from congenital abnormalities of the kidney and urinary tract (CAKUT) to oncogenic processes. Defining the relationship of PAX2 to human renal disease requires an appreciation of its fundamental role in renal development. Given the highly conserved nature of the PAX2 gene in vertebrates, it is not surprising that much of our understanding of PAX2 involvement in renal disease has been derived from animal models. The following review will outline the current evidence supporting involvement of PAX2 in the pathologic processes involving the kidney. 相似文献
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Andreas K. W. Vécsei Thomas Müller Edith C. Schratzberger Karl Kircher Heinz Regele Klaus Arbeiter Brigitte Schroth C. Aufricht 《Pediatric nephrology (Berlin, Germany)》2001,16(11):898-900
We report an 8-year-old Caucasian boy who presented with steroid-resistant nephrotic syndrome. Renal biopsy showed the cellular
variant of focal segmental glomerulosclerosis (FSGS). Within 1 year he received a series of therapies that have induced remission
in other patients with this disease, all to no avail (conventional-dose cyclosporin A, methylprednisolone pulse therapy, high-dose
cyclosporin A, and therapy with mycophenolate mofetil). He achieved remission after five sessions of plasma exchange. This
case argues for aggressive therapy of resistant nephrotic syndrome in the native kidney. Plasma exchange should be considered
as a possible rescue therapy arm in future study protocols.
Received: 14 August 2000 / Revised: 16 April 2001 / Accepted: 14 June 2001 相似文献
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Treatment of FSGS with plasma exchange and immunadsorption 总被引:1,自引:0,他引:1
Franke D Zimmering M Wolfish N Ehrich JH Filler G 《Pediatric nephrology (Berlin, Germany)》2000,14(10-11):965-969
In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be achieved with treatment. Currently, most children with FSGS are treated with cyclosporine and steroids after establishing steroid resistance, and approximately 60% of patients benefit from this therapy. For the remaining 40%, no generally approved therapeutic recommendations exist for children. We treated nine children with cyclosporine-resistant primary FSGS with plasma exchange (PE), two with relapsing FSGS after renal transplantation and seven with FSGS in their native kidneys. Three patients did not respond to PE, but five came into complete remission and one patient achieved partial remission. Three patients relapsed between 6 weeks and 2 years following cessation of PE, and were subsequently treated with plasma immunadsorption (PIA), which also reliably reduced proteinuria. The patients without response to PE tended to have a longer duration of the disease. We conclude that PE and PIA are a useful option for treatment of steroid- and cyclosporine-resistant FSGS, particularly if applied early in the course of the disease. Although more demanding on supportive resources, PIA seems preferable to PE, since there is no necessity for additional albumin or fresh-frozen plasma, as with PE. 相似文献