Genetics of Glomerular Basement Membrane Disorders

Abstract

The purpose of this review is to provide current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (GBM) (Alport syndrome (AS), thin basement membrane nephropathy (TBMN), hereditary angiopathy associated with nephropathy, aneurysms and muscle cramps (HANAC) syndrome and Pierson syndrome), as well as disorders involving genetic defects in cellular proteins that result in structural defects in GBMs (MYH9‐related disorders, Nail–Patella syndrome, NPS). All cases of AS and approximately 50% of cases of TBMN arise from mutations affecting a type IV collagen network composed of alpha;3, α4 and α5 type IV collagen chains. The cardinal clinical feature of these disorders is hematuria. HANAC syndrome is caused by mutations that affect type IV collagen networks made up of α1 and α2 type IV collagen chains and also presents with hematuria. In contrast, Pierson syndrome, which results from mutations in the gene encoding β2 laminin, is associated with proteinuria.

Key Concepts:

  • Important physiologic qualities of the glomerular capillary wall, such as high water flux and restricted transit of proteins, rely on specific extracellular matrix proteins and their interactions with other proteins and glomerular cells.

  • Alport syndrome and thin basement membrane nephropathy (TBMN), the major genetic disorders of glomerular basement membranes (GBM), arise from abnormalities in a type IV collagen network comprising heterotrimers of α3, α4 and α5 type IV collagen chains.

  • Extrarenal features of Alport syndrome (sensorineural deafness and ocular lesions) result from abnormal type IV collagen composition of cochlear and ocular basement membranes.

  • Other inherited disorders of glomerular basement membranes result from laminin mutations (Pierson syndrome), mutations affected cytoskeletal function (MYH9‐related disorders) or dysregulation of the synthesis of extracellular matrix proteins (nail‐patella syndrome).

Keywords: glomerular basement membrane; type IV collagen; Alport syndrome; thin basement membrane nephropathy; HANAC syndrome; Nail–Patella syndrome; LMX1B; Pierson syndrome; laminin

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Further Reading

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Kashtan CE (2011) Hereditary nephritis (Alport syndrome). In: Rose BD (ed.) UpToDate. MA: Wellesley.

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Kashtan CE (2011) Collagen IV‐related nephropathies (Alport syndrome and thin basement membrane nephropathy). In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews [www.genereviews.org]. Seattle: University of Washington.

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Kashtan, Clifford E(Mar 2012) Genetics of Glomerular Basement Membrane Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023849]