The science behind Alport syndrome
Alport syndrome is caused by variants in the genes COL4A3, COL4A4 or COL4A5. These genes are needed to make a specialised network called collagen IV-alpha 3,4,5.
This collagen is a core component of the glomerular basement membrane, a protein scaffold in the filtering blood vessels in the kidney. The glomerular basement membrane connects endothelial cells, which line the blood vessels and podocytes, specialised epithelial cells on the outside of the blood vessels. Together, these cells and the basement membrane form the glomerular filtration barrier.
Image description: healthy glomerulus
A healthy glomerulus: the glomeruli are the filtration units of the kidney. This diagram shows a loop of tiny blood vessels called capillaries surrounded by a capsule called the Bowman’s capsule.
Two blood vessels take blood in and out the glomerulus and they are connected by looped capillaries The capillaries filter the blood. The filtrate collects between the capillary loops and the Bowman’s capsule and passes into the proximal tubule. Through further processing in the nephron, the filtrate becomes urine which is eventually drains to the bladder.
Zooming in, we can see the capillaries are lined with porous endothelial cells surround by a membrane (the glomerular basement membrane or GBM), which contains collagen IV alpha 3,4 and 5. On top of this are the foot processes of specialised cells called podocytes. These podocytes contact each other via their foot processes and the gap between them is filled by the slit diaphragm, a specialised cell junction.
The endothelial cells with their pores, the GBM and the podocytes with their slit diaphragms make up the filtration barrier. In healthy tissue the GBM looks like a smooth thin flat line with the endothelial cells underneath and the discrete foot processes sat on top, like fingers around a tube.
Disruption of the glomerular filtration barrier is caused by variants in the COL4A3, COL4A4 or COL4A5 genes and this leads to progressive loss of kidney function, and ultimately to kidney failure. In the most severely affected individuals, a kidney transplant is required as a teenager or in their early 20s.
Variants in the Alport can also cause hearing loss and eye abnormalities in individuals with Alport syndrome.
Image description: diseased glomerulus
This is an image of a diseased glomerulus. The Bowman’s capsule around the capillaries and the blood vessels coming in and going out of the capsule look much like the healthy glomerulus. The significant changes are in the basement membrane, the GBM, surrounding the capillaries and the specialised podocytes that sit on top of them.
We see here that the porous endothelial cells look the same, but the GBM that sits on top becomes thickened, split and irregular and has protrusions extending from the podocyte foot processes pushing into it.
The foot processes become enlarged and flattened and lose the slit diaphragms they normally have between them. The thickened and irregular GBM, flattened foot processes and loss of the slit diaphragm stop the filtration of blood occurring as normal.
Information for the public
More information about Alport syndrome for patients, families and members of the public can be found on the Alport UK website.
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