Genetic Defects of the Glomerular Basement Membrane

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The glomerular basement membrane is a thin layer of extracellular membrane proteins that is an important part of the filtration barrier, particularly glomerular permselectivity, by preventing proteins from crossing into the filtrate. The major proteins in the GBM are laminin, type IV collagen, nidogen and the heparan sulphate proteoglycan agrin. Interestingly, in the past, I was taught that the highly negative charge on agrin played the major role in mediating charge selectivity. However, recent studies have shown that mutations in the gene encoding agrin, leading to a reduction in charge along the GBM, have no effect of glomerular function in mice. Similarly, deletion of agrin has little effect on permselectivity further suggesting that the role of the proteoglycans in selective filtration is minor at best.

There are two conditions associated with genetic defects in glomerular basement membrane proteins:

Syndrome
Gene(s) affected
Protein
Phenotype
Alports
Syndrome
COL4A3
COL4A4
COL4A5
Type IV
Collagen, α3, α4, α5 subunits
Initial
normal formation of GBM but eventually hematuria, proteinuria and eventual
ESRD with characteristic splitting of the GBM. COL4A5 mutations are commonest
and are X-linked. Other forms are autosomal.
Pierson
Syndrome
LAMB2
Laminin β2
Autosomal
recessive disorder with variable phenotype depending on the particular
mutation. However, ocular abnormalities (microcoria) are present at birth and
the majority of affected individuals progress to ESRD within the first few
weeks/months of life. Extrarenal manifestations including hypotonia and
neurodevelopmental defects have been reported.

Please see this excellent review in Nature Reviews Nephrology for further information.

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