Alport syndrome and Pierson syndrome: Diseases of the glomerular basement membrane
Introduction
Glomeruli are spheroid capillary tufts in the kidney cortex that filter the blood to generate the primary urine. This filtrate flows into the tubular segments of the nephron and then into the collecting ducts, which together convert the dilute primary urine into the final concentrated urine. Within the glomerulus is the glomerular basement membrane (GBM), a blanket-like extracellular matrix (ECM) that is situated between two cell types: specialized epithelial cells called podocytes that reside in the urinary space, and specialized fenestrated endothelial cells lining the glomerular capillaries (Fig. 1).
The GBM together with the podocytes and endothelial cells comprise the glomerular filtration barrier between the blood and the urine [1,2]. During glomerulogenesis, the GBM arises from fusion of separate basement membranes synthesized by the immature epithelial podocytes and glomerular endothelial cells [3]. Like all basement membranes [4], the GBM contains members of the four major classes of basement membrane proteins: collagen IV, laminin, heparan sulfate proteoglycan (primarily agrin, though perlecan is also present in the immature GBM [5]), and nidogen (isoforms 1 and 2) (Fig. 2) [[6], [7], [8]], though dozens of other matrix proteins are likely present [9,10], including nephronectin [11,12].
The GBM is of special interest for both nephrologists and geneticists because there are mutations in type IV collagen and laminin genes that cause human kidney disease [13]. Alport syndrome is caused by mutations that affect the major collagen IV network of the GBM, whereas Pierson syndrome is caused by mutations that affect the laminin network. This makes the GBM also a keen interest of biochemists, since the hundreds of known collagen IV and laminin mutations can provide valuable information about important structural and functional aspects. In addition, recent breakthroughs in super-resolution imaging have provided novel information about how the collagen IV and laminin networks are arranged within the GBM, leading to new insights about how these networks might function in glomerular filtration.
Section snippets
Collagen IV chains and assembly
The type IV collagen family consists of six α chains, α1-α6, and each is encoded by a separate gene (COL4A1-COL4A6). Like all other collagen chains, collagen IV chains contain a collagenous domain consisting of Gly-X-Y amino acid triplet repeats that allow the intertwining of three α chains into a triple helix. However, unlike fibrillar collagens that form stiff structures, network-forming collagen IV contains multiple interruptions of the Gly-X-Y repeats interspersed throughout the large
Laminin-521
The GBM's major laminin isoform is laminin-521 (LM-521), a cross-shaped heterotrimeric glycoprotein composed of the laminin α5, β2, and γ1 chains. LM-521 trimers are secreted by both podocytes and endothelial cells [66,67] and polymerize in the ECM to form separate lattice-like networks at each edge of the GBM. Polymerization of trimers into a network is directed by ternary interactions among the α5, β2, and γ1 chain laminin NH2-terminal (LN) domains [68,69]. This leaves the large laminin
Concluding thoughts
Both Alport syndrome and Pierson syndrome are caused by mutations that impact the structure and function of the GBM, yet the kidney aspects of these diseases are very different. Alport syndrome causes a gradual decline in kidney function, beginning with hematuria, but proteinuria begins later in the disease course. In stark contrast, Pierson syndrome and the related NPHS5 are congenital nephrotic syndromes with very high levels of proteinuria at or shortly after birth. Deciphering the
Acknowledgments
Our research into Alport syndrome and Pierson syndrome has been supported by NIH grants R01DK078314, R56DK100593, R01DK058366, and T32DK007126 and by grants from the Alport Syndrome Foundation-Pedersen Family-Kidney Foundation of Canada.
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Equal contributions.