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Marie Claire Gubler - One of the best experts on this subject based on the ideXlab platform.
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Oxford Medicine Online - Thin Glomerular Basement Membrane nephropathy and other collagenopathies
Oxford Medicine Online, 2018Co-Authors: Laurence Heidet, Bertrand Knebelmann, Marie Claire GublerAbstract:The discovery of a thin Glomerular Basement Membrane in a renal biopsy without any other abnormalities can be explained in a number of ways. This could be an early biopsy in a patient with Alport syndrome, or it could be an individual who is a carrier for an Alport gene. These carriers are at increased risk of significant renal disease in their lifetime and some have proteinuria as well as haematuria, so they can no longer be equated with the historic label of benign familial haematuria. Some families with a thin Glomerular Basement Membrane and haematuria inherited in an autosomal dominant fashion do not appear to have linkage to COL4 genes. Others have variable renal disease that has sometimes given rise to a label of mild but autosomal dominant Alport syndrome. This territory might also attract the label Basement Membrane 345 collagenopathy. Other uncommon conditions affecting the Glomerular Basement Membrane include nail patella syndrome.
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Inherited diseases of the Glomerular Basement Membrane
Nature Clinical Practice Nephrology, 2008Co-Authors: Marie Claire GublerAbstract:The Glomerular Basement Membrane (GBM) is a specialized form of Basement Membrane that has a major role in the maintenance of the Glomerular filtration barrier. Like all Basement Membranes, it contains four main components: type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. Different isoforms of these large molecules are produced. These isoforms have a tissue-specific distribution; in the mature GBM, the major type IV collagen molecule is the α3α4α5(IV) isoform, associated with laminin-521 (α5β2γ1), nidogen and agrin heparan sulfate proteoglycans. The importance of the GBM has been demonstrated by identification of hereditary Glomerular diseases linked to structural anomalies of its components; for example, type IV collagen in Alport syndrome and familial benign hematuria, and laminin in Pierson syndrome. Type III collagen, an interstitial collagen, accumulates within the GBM of patients with the nail–patella syndrome, and abnormal deposition of fibronectin, another extracellular matrix protein, is characteristic of so-called fibronectin nephropathy. Development of animal models of these diseases has facilitated precise analysis of pathogenic mechanisms, but no specific treatments are available. Therapeutic trials in Alport syndrome nephropathy are underway, following promising preliminary results obtained in rodent and canine models of the disorder. Here, Dr Gubler describes the pathogenesis of disorders that affect components of the Glomerular Basement Membrane, including type III and type IV collagen, laminin and fibronectin. Dr Gubler harnesses her considerable clinical experience to recommend diagnostic and management strategies for Alport syndrome, Pierson syndrome, nail–patella syndrome, benign familial hematuria/thin Basement Membrane nephropathy, and glomerulopathies caused by errant deposition of fibronectin and type III collagen. No specific treatments are available for inherited diseases in which mutation of genes that encode components of the Glomerular Basement Membrane (GBM) perturb its structure Hematuria is a major clinical feature of Alport syndrome, a progressive disease in which the structure of type IV collagen in the GBM is abnormal Alport syndrome can be inherited in an X-linked dominant, autosomal recessive or autosomal dominant manner Laminin glycoproteins are essential to the assembly of the GBM and mutations of LAMB2 , which encodes the β2 chain of laminin, lead to Pierson syndrome Deposition of type III collagen within the GBM is the hallmark of nail–patella syndrome and accumulation of this protein in the Glomerular extracellular matrix is also observed in rare nonsyndromic glomerulopathies Parietal and mesangial deposition of fibronectin also cause glomerulopathy
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inherited diseases of the Glomerular Basement Membrane
Nature Reviews Nephrology, 2008Co-Authors: Marie Claire GublerAbstract:Here, Dr Gubler describes the pathogenesis of disorders that affect components of the Glomerular Basement Membrane, including type III and type IV collagen, laminin and fibronectin. Dr Gubler harnesses her considerable clinical experience to recommend diagnostic and management strategies for Alport syndrome, Pierson syndrome, nail–patella syndrome, benign familial hematuria/thin Basement Membrane nephropathy, and glomerulopathies caused by errant deposition of fibronectin and type III collagen. The Glomerular Basement Membrane (GBM) is a specialized form of Basement Membrane that has a major role in the maintenance of the Glomerular filtration barrier. Like all Basement Membranes, it contains four main components: type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. Different isoforms of these large molecules are produced. These isoforms have a tissue-specific distribution; in the mature GBM, the major type IV collagen molecule is the α3α4α5(IV) isoform, associated with laminin-521 (α5β2γ1), nidogen and agrin heparan sulfate proteoglycans. The importance of the GBM has been demonstrated by identification of hereditary Glomerular diseases linked to structural anomalies of its components; for example, type IV collagen in Alport syndrome and familial benign hematuria, and laminin in Pierson syndrome. Type III collagen, an interstitial collagen, accumulates within the GBM of patients with the nail–patella syndrome, and abnormal deposition of fibronectin, another extracellular matrix protein, is characteristic of so-called fibronectin nephropathy. Development of animal models of these diseases has facilitated precise analysis of pathogenic mechanisms, but no specific treatments are available. Therapeutic trials in Alport syndrome nephropathy are underway, following promising preliminary results obtained in rodent and canine models of the disorder.
Mark Haas - One of the best experts on this subject based on the ideXlab platform.
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alport syndrome and thin Glomerular Basement Membrane nephropathy a practical approach to diagnosis
Archives of Pathology & Laboratory Medicine, 2009Co-Authors: Mark HaasAbstract:Abstract Context.—Alport syndrome and thin Glomerular Basement Membrane nephropathy (TBMN) are genetically heterogenous conditions characterized by structural abnormalities in the Glomerular Basement Membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen α3 [α3(IV)] and α4 chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the α5 chain of type IV collagen [α5(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport...
M. Bendayan - One of the best experts on this subject based on the ideXlab platform.
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High-Resolution Ultrastructural Study of the Rat Glomerular Basement Membrane in Aminonucleoside Nephrosis
Ultrastructural Pathology, 1996Co-Authors: S. Inoue, M. BendayanAbstract:In the initial stages of aminonucleoside nephrosis, functional alterations in the Glomerular Basement Membrane occur, as evidenced by the development of proteinuria. However, it has not been possible to observe important ultrastructural modifications at the level of the Basement Membrane, probably because the changes are taking place at the molecular level. In this study, by the use of high-resolution electron microscopy, an attempt was made to evaluate such changes in rat Glomerular Basement Membrane during acute aminonucleoside nephrosis. As previously reported, in control animals the Glomerular Basement Membrane is composed of a network of 4-nm-wide irregular anastomosing strands, referred to as “cords,” which are known to contain a core filament of type IV collagen surrounded by a “sheath” of other components, such as laminin and heparan sulfate proteoglycan (HSPG). The most conspicuous ultrastructural alteration of the nephrotic Glomerular Basement Membrane, recognizable only at high magnification, i...
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High-resolution ultrastructural study of the rat Glomerular Basement Membrane in long-term experimental diabetes.
Ultrastructural Pathology, 1995Co-Authors: S. Inoue, M. BendayanAbstract:The ultrastructure of the Glomerular Basement Membrane of the long-term diabetic and age-matched control rats was studied with the application of advanced high-resolution microscopy. By using the freeze substitution method for the preparation of the renal tissue, it was possible to observe that the Glomerular Basement Membrane in control and diabetic animals is composed of only a single lamina densa without the presence of a lamina lucida interna or externa. High-resolution electron microscopy of the diabetic Glomerular Basement Membrane showed significant alterations in its morphology and ultrastructure. First, the Basement Membrane in diabetic condition appeared to be split into two halves, endothelial and epithelial. In the epithelial half of the Membrane, the network of distinct strands referred to as cords, which were clearly present in the Glomerular Basement Membrane of age-matched control animals, became less distinct and showed a diffused appearance being evenly replaced by thin filaments. The op...
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Ontogenesis of Glomerular Basement Membrane: structural and functional properties.
Journal of Cell Biology, 1991Co-Authors: Michel Desjardins, M. BendayanAbstract:Protein A-gold immunocytochemistry was applied in combination with morphometrical approaches to reveal the alpha 1(IV), alpha 2(IV), and alpha 3(IV) chains of type IV collagen as well as entactin on renal Basement Membranes, particularly on the Glomerular one, during maturation. The results have indicated that a heterogeneity between renal Basement Membranes appears during the maturation process. In the glomerulus at the capillary loop stage, both the epithelial and endothelial cell Basement Membranes were labeled for the alpha 1(IV) and alpha 2(IV) chains of type IV collagen and entactin. After fusion, both proteins were present on the entire thickness of the typical Glomerular Basement Membrane. At later stages, the labeling for alpha 1(IV) and alpha 2(IV) chains of type IV collagen decreased and drifted towards the endothelial side, whereas the labeling for the alpha 3(IV) chain increased and remained centrally located. Entactin remained on the entire thickness of the Basement Membrane during maturation and in adult stage. The distribution of endogenous serum albumin in the Glomerular wall was studied during maturation, as a reference for the functional properties of the Glomerular Basement Membrane. This distribution, dispersed through the entire thickness of the Basement Membrane at early stages, shifted towards the endothelial side of the lamina densa with maturation, demonstrating a progressive acquisition of the permselectivity. These results demonstrate that modifications in the content and organization of the different constituents of Basement Membranes occur with maturation and are required for the establishment of the filtration properties of the Glomerular Basement Membrane.
Jeffrey H Miner - One of the best experts on this subject based on the ideXlab platform.
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The Glomerular Basement Membrane as a barrier to albumin
Nature Reviews Nephrology, 2013Co-Authors: Jeffrey H MinerAbstract:The Glomerular Basement Membrane (GBM) is the extracellular matrix component of the Glomerular filtration barrier; it is flanked by the podocyte and Glomerular endothelial cell layers The major GBM components are laminin-521, type IV collagen α3α4α5, nidogen, and the heparan sulphate proteoglycan agrin Mutations in COL4 genes that result in absence of the type IV collagen α3α4α5 network cause Alport syndrome, a hereditary nephritis accompanied by hearing defects Mutations in laminin β2 ( LAMB2 ) cause Pierson syndrome, a congenital nephrotic syndrome with associated eye and neurologic abnormalities Studies using mouse models of Pierson and Alport syndromes have shown that the defective GBM is more permeable to macromolecules than is the normal GBM, suggesting that it has a role in permselectivity The Glomerular Basement Membrane (GBM) is the central, non-cellular layer of the Glomerular filtration barrier that is situated between the two cellular components—fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule—laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen—which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the Glomerular filtration barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in Glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity. The Glomerular Basement Membrane (GBM) is the central layer of the Glomerular filtration barrier and is situated between endothelial cells and podocyte foot processes. The functional importance of the GBM versus that of podocytes and endothelial cells for establishing the Glomerular filtration barrier to albumin is still debated. This Review discusses the proposed mechanisms whereby the GBM serves as the major albumin barrier and describes two genetic kidney diseases that target GBM components.
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The Glomerular Basement Membrane.
Experimental Cell Research, 2012Co-Authors: Jeffrey H MinerAbstract:The kidney's Glomerular filtration barrier consists of two cells-podocytes and endothelial cells-and the Glomerular Basement Membrane (GBM), a specialized extracellular matrix that lies between them. Like all Basement Membranes, the GBM consists mainly of laminin, type IV collagen, nidogen, and heparan sulfate proteoglycan. However, the GBM is unusually thick and contains particular members of these general protein families, including laminin-521, collagen α3α4α5(IV), and agrin. Knockout studies in mice and genetic findings in humans show that the laminin and type IV collagen components are particularly important for GBM structure and function, as laminin or collagen IV gene mutations cause filtration defects and renal disease of varying severities, depending on the nature of the mutations. These studies suggest that the GBM plays a crucial role in establishing and maintaining the Glomerular filtration barrier.
Sagripanti S - One of the best experts on this subject based on the ideXlab platform.
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Thin Glomerular Basement Membrane disease
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia, 2008Co-Authors: Giovanni M. Frascà, Emilio Balestra, Fanciulli E, Freddi P, Mazzucchelli R, Montironi R, D'arezzo M, Sagripanti SAbstract:Abstract Thin Glomerular Basement Membrane disease (TBMD) is a hereditary nephropathy characterized by thinning of the Glomerular Basement Membrane evinced by electron microscopy and, clinically, by isolated hematuria without extrarenal manifestations. Familial aggregation is found in 50-60% of cases, with autosomal dominant transmission. TBMD is considered to belong to the type IV collagen spectrum of diseases, since heterozygous mutations of the COL4A3 or COL4A4 gene have been detected in more than 30% of patients. The disease is found in 1-2% of biopsies, but the prevalence in the general population may be higher. The differential diagnosis with Alport's syndrome may be difficult and requires accurate family investigations, immunohistochemical evaluation of type IV collagen alpha chains in renal tissue and, if appropriate, genetic studies. Progression towards chronic renal failure, although rare, has been reported in some patients, and may be related to the phenotypical variability of COL4A3/COL4A4 mutations, to a missed Alport syndrome, or to superimposed Glomerular disease. Patients suffering from TBMD and affected relatives should be periodically examined for signs of disease progression and informed about the possibility of transmitting the autosomal recessive form of Alport's syndrome.