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Primer: strategies for identifying genes involved in renal disease

Nature Clinical Practice Nephrology volume 4, pages 265–276 (2008)Cite this article

Abstract

The globally increasing number of patients with end-stage renal disease urges the identification of molecular pathways involved in renal pathophysiology, to serve as targets for intervention. Moreover, the identification of genetic risk factors or protective genes can aid tailored therapy. Tools that can be used to identify genes involved in renal disease include gene expression arrays, linkage analysis and association studies. Arrays are a powerful and widely used approach to the analysis of gene transcription and protein expression, whereas linkage analysis and association studies link disease susceptibility to particular genetic regions. Animal models are available to pinpoint the disease-associated genes. Candidate genes so far identified in renal disease include those encoding the podocyte proteins nephrin and podocin, the transcription factor WT1, the calcium channel TRPC6 and the enzyme phospholipase C-epsilon-1 (in congenital nephrotic syndrome and focal segmental glomerulosclerosis), and carnosinase (in diabetic nephropathy). In addition, linkage studies have identified chromosomal regions implicated in systemic lupus erythematosus, diabetic nephropathy and familial IgA nephropathy. Future studies will elucidate the emerging role of epigenetic regulation of gene expression in renal disease.

Key Points

  • Tools for identifying genes involved in renal disease include gene expression arrays, linkage analysis and association studies

  • Gene expression arrays are powerful and widely used tools; when confounding influences are minimized by use of a robust study design, these arrays have reasonable reproducibility

  • Linkage analysis and association studies have implicated several regions of the genome in the pathogenesis of complex renal disorders

  • The genetic defects responsible for some hereditary renal diseases, such as familial focal segmental glomerulosclerosis and nephrotic syndrome, have been identified

  • Identification of candidate renal disease genes can generate prognostic markers to guide tailored therapy and provide novel targets for intervention

  • Altered gene methylation has been observed in renal disease; further studies are required to elucidate the role of this and other forms of epigenetic modification in this setting

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Figure 1: Number of papers reporting use of gene expression arrays published per year since 1995, underlining the rapidly growing popularity of this technology.
Figure 2: Hypothetical design of integrated multiple-level cellular profiling for the identification of candidate renal disease pathways.
Figure 3: Overview of renal-damage-related quantitative trait loci in the rat, by chromosome.
Figure 4: Overview of components associated with the glomerular slit diaphragm and the podocyte cytoskeleton in which mutations have been identified in human congenital nephrotic syndrome and/or focal segmental glomerulosclerosis.

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Acknowledgements

The authors would like to thank Dr Jessica Caprioli and Dr Marina Noris for critically reading the manuscript. This work, as part of the European Renal Genome (EuReGene) project, was supported by the European Union Sixth Framework Programme (FP6), grant number LSHG-CT-2004-005085. Charles P Vega, 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. A Benigni is Head of the Department of Molecular Medicine, MH de Borst is a Post-Doctoral Research Fellow on the European Renal Genome (EuReGene) project, and G Remuzzi is Director of the Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.,

    Martin H de Borst, Ariela Benigni & Giuseppe Remuzzi

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Correspondence to Martin H de Borst.

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Supplementary Table 1

Overview of renal damage-related QTLs and their chromosomal location, as reported in the literature. (DOC 44 kb)

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de Borst, M., Benigni, A. & Remuzzi, G. Primer: strategies for identifying genes involved in renal disease. Nat Rev Nephrol 4, 265–276 (2008). https://doi.org/10.1038/ncpneph0785

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