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Inherited diseases of the glomerular basement membrane

Nature Clinical Practice Nephrology volume 4, pages 24–37 (2008)Cite this article

Abstract

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.

Key Points

  • 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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Figure 1: Type IV collagen.
Figure 2: Laminin α5β2γ1.
Figure 3: Electron microscopy images of renal tissue from patients with Alport syndrome.
Figure 4: Immunohistological analysis of the renal distribution of type IV collagen chains.
Figure 5: Immunohistological analysis of the distribution of the α5(IV) collagen chain.

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale and the Centre de référence Maladies Rénales Héréditaires de l'Enfant et de l'Adulte and by grants from the Association pour l'Utilisation du Rein Artificiel and the Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques. I also thank E Le Gall for excellent technical assistance with figure preparation. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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  1. INSERM U574, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris F75015, France gubler@necker.fr

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  1. MC Gubler is Emeritus Director of Research at the Institut National de la Santé et de la Recherche Médicale, INSERM U574, Hôpital Necker-Enfants Malades, Paris F75015, and Université Paris Descartes, Paris F75006, France.,

    Marie Claire Gubler

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Gubler, M. Inherited diseases of the glomerular basement membrane. Nat Rev Nephrol 4, 24–37 (2008). https://doi.org/10.1038/ncpneph0671

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