Brenner and Rector's The Kidney, 8th ed.

CHAPTER 39. Inherited Disorders of Podocyte Function

Jochen Reiser   Martin R. Pollak



The Glomerular Filtration Barrier, 1379



Podocyte Injury and Proteinuria, 1379



Cytoskeletal Make-up of Podocytes, 1380



F-actin Forms the Structural Support in Podocyte Foot Processes, 1381



Actin-associated Proteins in Podocytes, 1381



The Slit Diaphragm Complex Coupled to the Cytoskeleton, 1381



Connection between Foot Processes and the Cytoskeleton, 1382



Cytoskeletal Alterations during Podocyte Damage, 1382



Inherited Disorders of Podocyte Function, 1382



Slit Diaphragm, 1382



Cytoskeleton, 1384



Other Forms of Disease, 1385



Syndromic Disease, 1385

The glomerular epithelial cells, or podocytes, are unique cells with an unusual octopus-like topology. These cells and the unique junctional complex between them form the distal barrier to protein filtration by providing charge and size selectivity. Until fairly recently, the location, structure, and degree of differentiation of podocytes hampered analysis of this cell type. However, in the past decade, there has been considerable progress in understanding the biology of these cells and their contribution to human disease. Cultured podocytes with a differentiated phenotype have become available and are now a standard reagent.[1] Subsequently, several groups demonstrated that mutations in slit-diaphragm protein genes led to disease phenotypes in humans and animal models, some leading to severe nephrosis, others to slowly progressive proteinuria and renal insufficiency.[2] Since then, the podocyte has attracted considerable attention, but many aspects of the biology of these cells remain puzzling. Despite substantial progress in understanding patterns of podocyte damage and the now well-accepted notion that glomerular function fails without functional podocytes, there is no clearly defined common pathway leading to podocyte failure. Descriptions of histopathological changes rather than altered genetic and biochemical pathways therefore still remain the standard method for classifying “podocytopathies”. Nevertheless, identification of inherited gene defects affecting podocyte structure and function have proven helpful in understanding podocyte function as well as podocyte disease (Fig. 39-1 ).



FIGURE 39-1  Schematic representation of podocyte foot processes (FP) and the interposed slit diaphragm (SD) covering the outer aspect of the glomerular basement membrane (GBM). Many of the indicated proteins have been shown to be mutated in human or murine forms of nephrotic syndrome or focal segmental glomerulosclerosis, or both.




The glomerular filtration barrier functions to retain plasma proteins in the blood on the basis of molecular charge and size.[3] To move from the vascular into the urinary space, molecules pass though three distinct structures.[4] The first is a fenestrated endothelium decorating the glomerular capillaries. The fenestrae between the endothelial cells are 70 nm to 100 nm in diameter. On the surface, these glomerular endothelial cells carry a complex of negatively charged sialoproteins and proteoglycans (glycocalyx).[5] Although the negative charge of the glycocalyx constitutes a potential barrier retarding anionic macromolecules, there is no evidence so far for such a role of the endothelial glycocalyx. The second structure is the glomerular basement membrane, a thin sheet of specialized extracellular matrix composed of four major components: laminin, type IV collagen, nidogen/entactin, and proteoglycans.[6] During glomerulogenesis, the glomerular basement membrane is built up in a combined effort of the underlying endothelial and overlying podocytes. As the case for the fenestrated endothelium, it is thought that the presence of negatively charged molecules within the glomerular basement membrane serve as a barrier retarding anionic macromolecules. [7] [8] The third structure consists of podocytes and the interposed glomerular slit diaphragm.[9]

Podocytes are non-replicating polarized epithelial cells that originate from precursor mesenchymal cells.[10] During nephrogenesis, these cells undergo modification from a classic epithelial cell phenotype to a highly specialized mesenchymal type of cell.[11] The manner in which they wrap around the glomerular capillaries has often led to comparisons with pericytes. Podocytes cover the external surface of adjacent capillaries and interact with the glomerular basement membrane through finger-shaped extensions called ped-icels or foot processes. The basal surface of podocyte foot processes is anchored in the glomerular basement membrane via integrin cell matrix receptors in particular α3/b1-integrins and a/b-dystroglycans. [12] [13] Podocyte foot processes interdigitate in a complex manner forming an intricate network surrounding the glomerular capillaries. Adjacent foot processes bridge their narrow 300-400 angstrom-wide filtration slits by an electron-dense membrane-like structure, the slit diaphragm.[14] The slit diaphragm is a thin porous membrane composed of a number of molecules. This slit diaphragm multi-protein complex is thought to form the major determinant of the size permselectivity of the glomerular filtration barrier, allowing for the passage of water and solutes from the blood into the kidney ultrafiltrate while restraining the loss of larger plasma molecules.[15]

Podocyte Injury and Proteinuria

Glomerular proteinuria is a hallmark of glomerular disease and results from an increased permeability of the glomerular filtration barrier.[16] Normally, proteins larger than albumin do not enter the urinary space whereas lower molecular weight proteins are filtered and partially reabsorbed in the proximal tubule. Normal excretion levels of protein into the urine vary between 0 mg/d and 150 mg/d. Proteinuria is clinically defined as a protein loss into the urine of more than 150 mg/d. Levels of 3 (or 3.5) grams of urinary protein per day are generally used to define “nephrotic-range” proteinuria. In many forms of glomerular diseases, proteinuria is correlated with podocyte injury.[17]However, this is not always the case.[18] The complexity of interactions among podocyte proteins provides several targets for podocytopathies and disruption of the glomerular filtration barrier. Loss of the integrity of the intricate structures of the podocyte can be seen in patients with nephrotic syndrome, who clinically present with marked proteinuria and possibly systemic hypertension. Electron microscopic examination of kidney biopsy specimens reveals the loss of normal podocyte foot process structure, resulting in a flattened podocyte phenotype, where foot processes form an epithelial monolayer lacking a functional slit diaphragm (foot process effacement).[19] If early structural changes of podocytes are not reversed, severe and progressive glomerular damage is more likely to develop.[20] This involves podocyte vacuolization, pseudocyst formation, and detachment of podocytes from the glomerular basement membrane. Because highly differentiated podocytes are unable to replicate, the damage and loss of single podocytes leads to podocyte depletion over time, which is a major determinant in the development of glomerulosclerosis and chronic kidney failure.[21]

Cytoskeletal Make-up of Podocytes

The cytoskeleton, a structural system of fibers, must serve static and dynamic functions of a cell.[22] Dependent on the physiological role of the particular cell type, the cytoskeletal organization varies. In general, it consists of three discreet sets of ultrastructural elements: microfilaments (7 nm to 9 nm in diameter), intermediate filaments (10 nm), and microtubules (24 nm).[23] All types of fibers are assembled in a coordinated fashion from small protein subunits. In the podocyte, the cytoskeleton responds to the unique challenges of the filtration barrier with several levels of structural organization, represented by different molecular constituents.[16] A well-developed cytoskeleton supports the defined shape of the podocyte as well as their cellular extensions.

Microtubules and intermediate filaments are the scaffold of podocyte major processes and the cell body.[24] Podocyte foot processes contain a dense network of actin filaments that are connected to the slit membrane complex at the baso-lateral membrane via an array of linker proteins such as CD2AP[25] and NCK. [26] [27] The actin cytoskeleton at the sole plate of the foot processes is functionally linked to the glomerular basement membrane via focal adhesion proteins, integrins, and dystroglycans.[28] Functionally, the regulation of focal adhesions and the slit diaphragm complex are connected by regulatory proteins such as integrin-linked kinase. [29] [30]

Two populations of actin are found in foot processes: a thin cortex of actin filaments beneath the cell membrane and actin bundles, which are densely accumulated in the center of foot processes.[31] Actin filaments form loop-shaped bundles at the arch of foot processes. The bends of these arches are located centrally at the transition to the primary processes and may readily be connected to the microtubules by microtubule-associated proteins. Peripherally, actin bundles appear to be anchored in the dense cytoplasm associated with the cell membrane close to the foot process sole plate.

The structural integrity of the foot process is crucial for providing stability between the slit diaphragm and the cell-matrix contacts of podocytes. Keeping the filtration slits open and foot processes adherent on the glomerular capillaries has resulted in the development of a specialized cytoskeletal organization in podocyte foot processes. The primary function of the foot process cytoskeleton is the coupling of the slit membrane multiprotein complex with adhesion of the foot process base to the glomerular basement membrane.[32] Glomerular filtration is a dynamic process and requires a combination of mechanical strength and flexibility.[33] The cytoskeletal organization of foot processes allows contractile functions to adapt to cyclic distensions of the glomerular capillaries, which occurs during glomerular filtration.[34] The role of the major processes is to provide leverage to keep glomerular capillaries open and to connect the podocyte cell bodies and the foot processes allowing protein trafficking and vesicular transport.[16]

The importance of the podocyte cytoskeleton is already apparent during glomerulogenesis. The expression of the podocyte-specific microfibrils appears to be a prerequisite for proper foot process development. During the capillary loop stage, when the vasculature invades the glomerular precursors, the cytoskeleton of the podocytes undergoes remodeling. Epithelial podocyte precursor cells are transformed into cells with a mesenchymal phenotype that coincides with the opening of the filtration slits and the formation of foot processes.[35] The induction of the intermediate microfilament vimentin is followed by the development of actin-rich branched cellular processes, which give rise to the foot process interdigitation of the mature filtration barrier. This genetic program is still operative in cell-cultured podocytes where a similar sequence of cytoskeletal rearrangements can be observed during differentiation.[1]

F-actin Forms the Structural Support in Podocyte Foot Processes

Microfilaments are the predominant cytoskeletal constituent of the foot process. The individual subunits of actin are known as globular actin (G-actin), whereas the filamentous polymer composed of G-actin subunits (a microfilament), is called F-actin. The microfilaments are the thinnest component of the cytoskeleton, measuring 7 nm in diameter. Similar to microtubules, actin filaments are polar, with a rapidly growing plus (+) or barbed end and a slowly growing minus (-) or pointed end.[36] The terms barbed and pointed end are adapted from the arrow-like shape of microfilaments with the associated motor domain of myosin as seen in electron micrographs. Filaments elongate approximately 10 times faster at the plus (+) than at the minus (-) end. This phenomenon is known as the treadmill effect. The process of actin polymerization, nucleation, starts with the association of three G-actin monomers into a trimer. ATP-actin then binds the plus (+) end, and the ATP is subsequently hydrolyzed (half time ∼2 seconds) and the inorganic phosphate released (half time ∼6 minutes), which reduces the binding strength between neighboring units and generally destabilizes the filament. ADP-actin dissociates from the minus end and the increase in ADP-actin stimulates the exchange of bound ADP for ATP, leading to more ATP-actin units. This rapid turnover is important for the cell's movement and supports the dynamic features of the foot processes. End-capping proteins such as CapZ prevent the addition or loss of monomers at the end of the filament where actin turnover is unfavorable.

The protein cofilin binds to ADP-actin units and promotes their dissociation from the minus end and prevents their reassembly.[37] The protein profilin reverses this effect by stimulating the exchange of bound ADP for ATP.[38] In addition, ATP-actin units bound to profilin will dissociate from cofilin and are then free to polymerize. Another important component in filament production is the Arp2/3 complex, which nucleates new actin filaments while bound to existing filaments, thus creating a branched network.[39] All of these three proteins are regulated by cell signaling mechanisms.

Actin-Associated Proteins in Podocytes

F-actin is a highly dynamic structure with a polar orientation, allowing for rapid growth, branching, and disassembly. Actin filaments are bundled in closely packed parallel arrays or are loosely associated in networks. Bivalent actin cross-linking molecules from the calponin homology-domain superfamily (i.e., α-actinin and dystrophin) define the level of actin packing. Associated motor proteins like myosin allow for isometric or isotonic contraction of the bundles in muscle and nonmuscle cells.[40] Podocytes contain several actin-associated proteins such as α-actinin-4 and synaptopodin. [40] [41] [42] [43] Synaptopodin is a proline-rich protein and is required for proper regulation of foot process dynamics as mice lacking synaptopodin have delays in recovery from experimental foot process effacement. [44] [45] More recently, synaptopodin has been shown to prevent the small GTPase Rho A from Smurf-mediated ubiquitination and subsequent degradation.[46]

α-Actinin is a ubiquitously expressed protein that is regarded as the ancestral molecule within a family of actin-binding proteins comprising spectrin, dystrophin, and utrophin.[47] Muscle and non-muscle isoforms of α-actinin have been described. The four α-actinin genes encode highly homologous proteins that form head-to-tail homodimers or heterodimers.[48] Although the best-defined function of α-actinin is to crosslink and bundle actin filaments, α-actinin has also been found to interact with a large and diverse set of other proteins. In skeletal and cardiac muscle, α-actinin is found at the Z disk, where it crosslinks anti-parallel actin filaments from adjacent sarcomeres. In non-muscle cells, α-actinin is involved in the organization of the cortical cytoskeleton and is also found along stress fibers and in focal contacts, where it interacts with a variety of cytoskeletal and membrane-associated proteins. α-Actinin may link the actin cytoskeleton to the cell membrane via interactions with transmembrane receptors or indirectly, via cytoskeletal proteins.[47]

The Slit Diaphragm Complex Coupled to the Cytoskeleton

Based on electron microscopic studies of perfusion-fixed rodent kidneys, Rodewald and Karnovsky originally proposed an isoporous zipper-like structure model for the slit diaphragm.[14] Until recently, the molecular nature of the slit diaphragm remained a doggedly persistent mystery in glomerular cell biology. Nephrin was the first molecule to be localized to the extracellular portion of the slit diaphragm.[49] Nephrin is essential for the development and function of the normal glomerular filter, and children born with a nephrin gene mutation develop severe urinary protein loss. The NPHS1-deficient disorder, as well as inactivation of the mouse nephrin gene, lead to an absence of the slit dia-phragm.[50] In addition to nephrin, P-cadherin,[15] the nephrin homolog Neph1,[51] and the large cadherin-like protein FAT1 [52] [53] (the human homologue to the Drosophila tumor suppressor fat) have been localized to the extracellular portion of the slit diaphragm. Nephrin is a type I transmembrane protein with both structural and signaling functions. Its intracellular domain is rich in serine and tyrosine residues that can be phosphorylated.[54]Engagement of the nephrin ectodomain induces transient Fyn kinase catalytic activity that leads to nephrin phosphorylation on specific nephrin cytoplasmic domain tyrosine residues. This nephrin phosphorylation event results in recruitment of the adapter protein Nck and assembly of actin filaments in an Nck-dependent fashion.[26] Considered in the context of the role of nephrin family proteins in other organisms and the integral relationship of actin dynamics and junction formation, these observations establish a function for nephrin in regulating actin cytoskeletal dynamics. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings suggest a physiological signaling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes.[27] Intracellularly, nephrin associates with podocin, CD2AP, Neph1, and the ion channel TRPC6.[55] Extracellularly, nephrin molecules may form protein-protein interactions across the filtration slit.[56] Evidence for extracellular homophilic interaction of nephrin and hetero-philic interactions of nephrin and Neph1 has recently been obtained.[57]

On the lateral sides of the foot processes, the cytoskeleton is linked to the slit diaphragm complex. ZO-1,[58] catenins,[15] and CD2AP[25] serve as adapter molecules between the transmembrane slit diaphragm molecules nephrin and P-cadherin and the actin filaments. The inactivation of CD2AP in mice causes an early-onset form of nephrotic syndrome.[25] Because the first function attributed to CD2AP was as an adapter molecule to the cytoskeleton in the immunological synapse, it is intriguing to draw similarities with CD2AP function in podocytes.[59] More recently, CD2AP was also shown to possess TGF beta signaling functions in podocytes.

Connection between Foot Processes and the Cytoskeleton

A negatively charged cell surface coat is present on podocyte foot processes. Subplasmalemmal actin is connected to an array of transmembrane molecules generating a negative charge area of podocytes. The sialogycoprotein podocalyxin contributes significantly to this negative surface charge. [60] [61] [62] It has been suggested that the negative charge of podocalyxin repulses proteins during filtration and also functions to keep the filtration slits in between adjacent foot processes open.[63] For this function, a tethering of podocalyxin to the subplasmalemmal actin network is required. The molecular constituents of this adapter complex have been defined.[64] Ezrin, a member of the ezrin/radixin/moesin family of adapter molecules interacts with the cytoplasmic domain of podocalyxin at the apical area of podocyte foot processes.[64] Ezrin is also known as a marker for damaged podocytes.[65] Na+/H+exchanger-regulatory factor 2 (NHERF2) was found to be a second member of the podocalyxin-actin complex.[66] NHERF2 binds via the NH2-terminal ERM binding region to Tyr-567 phosphorylated ezrin. Treatment of rats with puromycin or sialic acid is associated with dephosphorylation of ezrin and uncoupling of ezrin from the actin cytoskeleton. Neutralization of the negative podocalyxin surface charge with protamine sulfate results in a disruption of the intact NHERF2/ezrin complex from the cytoplasmic domain of podocalyxin, but leaves the complex connected to actin filaments.

The transmembrane endocytotic receptor glycoprotein 330/megalin, involved in protein uptake in epithelial cells, interacts with a member of the MAGUK protein family, Magi-1.[67] MAGUKs are involved in the clustering of molecules to defined membrane domains. Magi-1 serves as a multi-docking protein in the podocyte cell membrane to the actin cytoskeleton via a-actinin-4 and synaptopodin.[67] The Magi-1 splice isoforms found in podocytes appear to confer an association with the actin cytoskeleton.

Cytoskeletal Alterations during Podocyte Damage

Foot process effacement, also referred to as process simplification, retraction, or fusion, affects three aspects in the podocyte.[68] Foot process effacement results in the alteration of the slit diaphragm and in a mobilization of the cell matrix contacts.[69] Foot process effacement is accompanied by an increase in cytoskeletal density, reflected by a layer of electron-dense bundles at the sole of the foot process.[19] Dense bodies, serving as crosslinkers for microfilaments in smooth muscle cells,[70] have been discovered in the basal actin network of effaced foot processes.[69] Disruption of actin filaments and a transient dispersion of the microfilament structure in podocyte foot processes has been reported in puromycin nephrosis[71] and in complement-mediated injury.[72] Whether these structural alterations represent a compensatory response of the podocyte to oppose to an increase in capillary distending forces or as a reparative mechanism of podocyte damage is still undergoing scientific investigation.


Inherited disorders of podocyte function can be classified in several ways: by clinical syndrome, by mode of inheritance, by biological perturbation, and by the specific gene disrupted. In the discussion that follows, these diseases are organized by gene, and the list of genes in turn is organized (to the extent possible) by the putative biological function ( Table 39-1 ).

TABLE 39-1   -- Slit Diaphragm and Podocyte-associated Disease

Clinical Disorder




Gene Product

Age of Onset

OMIM Number[*]

Congenital NS of the Finnish type (CNF)







Steroid-resistant NS/FSGS


1q 25-31



3 Months to adulthood









FSGS/diffuse mesangial sclerosis




Phospholipase C epsilon

















Syndromic podocyte disorders

Denys-Drash syndrome (DDS)







Frasier syndrome (FS)







Nail-Patella syndrome (NPS)


9q 34





Pierson syndrome


3p 21


Laminin-β2 chain



Fabry disease




α-galactosidase A




FSGS, focal segmental glomerulosclerosis.



OMIM: Online Mendelian Inheritance in Man.[201]


Slit Diaphragm


Defects in the nephrin gene NPHS1 lead to the most clinically severe and earliest onset of the inherited podocytopathies.[49] The associated clinical syndrome, congenital nephrotic syndrome (CNS), also frequently referred to as congenital nephrotic syndrome of the Finnish type, is characterized by autosomal recessive inheritance and onset at birth. (In fact, abnormal glomerular filtration can be detected prenatally as an increase in maternal alpha-feto-protein.) Recognition of the clinical and pathologic features of CNS preceded the identification of nephrin by several decades.[73] Neonates with defective maternal and paternal nephrin alleles excrete on the order of 20 grams of urine protein per day. Affected infants are critically ill from the effects of nephrosis and hypoalbuminemia, and require intensive support to live. Treatment consists of aggressive supportive care until an age at which nephrectomy and renal transplantation (typically using a parent as the kidney donor) can be performed. In the absence of treatment, infants die, typically from the complications of severe nephrosis (e.g., infection, thrombosis), rather than kidney failure. In the past, bilateral nephrectomy was typically preferred, although some centers now perform unilateral nephrectomy prior to transplantation, allowing reduction in the degree of nephrosis while preserving some kidney function. [74] [75] [76] [77] [78]

NPHS1 was cloned by positional methods using human pedigrees. Nephrin, the NPHS1 gene product, is a large transmembrane protein with a large extracellular domain, a single membrane-spanning segment, and a short intracellular tail that appears to be important in a number of signaling pathways. It also plays a critical structural role in the slit diaphragm.[79] Its expression is largely podocyte restricted, although low levels of expression have been reported elsewhere.[80] CNS is particularly common in Finland, as are a number of rare recessive diseases. Two different point mutations account for the vast majority of CNS in this locale. These mutations are referred to as Fin-major and Fin-minor.[49] Both of these mutations lead to premature termination of the encoded protein. Fin major refers to two nucleotide deletion (nucleotides 121 and 122) leading to a frameshift. Fin minor, the rarer of the two common Finnish alleles, describes a premature termination codon at residue 1109. CNS is seen worldwide. More than 70 mutations in nephrin have been identified to date, including missense mutations as well as truncation and frame-shift mutations. [81] [82] [83] [84] [85] [86] There is a high incidence of congenital nephrotic syndrome in Old Order Mennonites in Pennsylvania. Two disease-associated alleles have been observed in this population where the incidence of CNS is 1 in 500 live births.[87]

In addition to truncation mutants, a large number of missense mutations in NPHS1 have been described. Several of these have been studied biochemically. Most mutations seem to alter proper targeting of nephrin to the slit diaphragm and lipid rafts. In cell culture, chemical chaperone therapy is able to restore targeting of several mutant forms of nephrin to the cell surface. [88] [89]

Nephrin has been shown to associate with several other proteins with proven or suspected roles in glomerular function. These interacting proteins include CD2AP and podocin. Several nephrin homologs have been identified, including NEPH-1, NEPH-2, and NEPH-3.[51] Mice lacking the Neph1 develop a CNS like phenotype, as do mice with targeted disruption in the nephrin gene. [50] [90] [91] [92] Despite the existence of close homologs, nephrin appears to have a non-redundant function, given the severe human and mouse “knockout” phenotypes.

The development of proteinuria is seen in a significant percentage of CNS children after renal transplantation. In general, this appears to be the result of the development of de novo anti-nephrin antibodies in the recipient. [93] [94]However, one recent report described a patient with recurrent proteinuria, absence of anti-nephrin antibodies, and a positive in vitro assay for serum glomerular permeability factor.[95]

Prior to the identification of the NPHS1 gene, high concentrations of alpha-feto-protein were used for the prenatal diagnosis of CNS in Finland. However, in Finland, where two mutations account for 95% of disease, antenatal genetic testing is now readily available. Heterozygosity for nephrin mutations in the fetus can lead to in utero proteinuria and elevated alpha-feto-protein, leading to potential false positives when this is used as a prenatal test, rather than genetic testing. [96] [97] [98] [99]

A recent report described muscular dystonia and athetosis in several CNS infants with NPHS1-associated disease. These neurologic deficits were severe and persisted even on those receiving dialysis or kidney transplantation, suggesting that these features may be a part of the spectrum of NPHS1-associated disease.[100]

Several groups have developed nephrin-deficient mouse models. [50] [91] [92] In addition to confirming the essential and non-redundant role of nephrin in podocyte function, analysis of these mice suggest that nephrin is not critical to glomerular development.

One study has addressed the possible involvement of NPHS1 in minimal change disease.[101] Resequencing of the NPHS1 gene in adults with a documented history of childhood MCD showed a high frequency (about 20%) of heterozygous non-conservative amino acid changing variants, compared with a control group. Thus this small study, not yet replicated, suggests that nephrin mutations may also contribute to increased susceptibility to the development of MCD.

Do nephrin polymorphisms play any role in modifying the renal response to forms of injury other than CNS? One recent study investigated the possible role of three common coding sequence missense variants in NPHS1 (cSNPs) on the degree of proteinuria and renal function decline. An association with one NPHS1 variant (G349A) and heavier proteinuria and faster renal function decline in IgA nephropathy was reported.[102] The nephrin locus does not appear to have a major role in the genetic susceptibility to diabetic nephropathy.[103]


The podocin gene NPHS2 was cloned by positional methods, similar to the methodology used to clone NPHS1.[104] Prior to these studies, childhood steroid-resistant nephrotic syndrome (SRN) was not generally recognized to be an inherited disease. However, by analysis of multiple families in which SRN segregated as a recessive trait, a previously unknown gene located at human chromosome 1p25-31 NPHS2, was identified. Podocin is an integral membrane protein with a single hairpin-like transmembrane domain and intracellular C- and N-terminal tails. Podocin, a 42 kD, 383 amino-acid protein, localizes to the slit diaphragm and interacts directly with nephrin and CD2AP.[105]

Podocin-associated disease is recessive. Affected individuals inherit a defective NPHS2 gene from both parents. A large and increasing number of putative disease-causing mutations (over 50) have been identified, and include missense mutations as well as mutations that cause premature truncation of the protein. [106] [107] [108] [109] [110] Although several mutations (e.g., R138Q) have been reported in several families without known common ancestors, there are no major mutations accounting for most disease (unlike the case with the nephrin gene NPHS1). Most of the published studies of NPHS2 genetics have focused on pediatric disease. However, podocin-mediated disease can present in adolescence or adulthood.[111]

Of the various focal segmental glomerulosclerosis (FSGS)/NS disease-associated genes, mutations in the podocin gene appear to be by far the most common. In about 50% of families with steroid-resistant nephrotic syndrome and apparent autosomal recessive inheritance, disease is linked genetically to the NPHS2.[112] This also provides evidence of the existence of other yet unknown disease genes.

In sporadic steroid-resistant disease (biopsy-proven FSGS or non-biopsied disease), presumed pathogenetic mutations in NPHS2 have been reported to be responsible for 10% to 30% of disease. [112] [113] The differences in frequency likely reflect both differences in geography as well as different inclusion criteria for the various studies.

The typical course in NPHS2-associated disease is progression to ESRD. Patients with NPHS2-associated disease have a much lower rate of recurrent disease in renal allografts than do patients with “idiopathic FSGS”. [112] [114] [115] [116] However, recurrent disease does occur, though the mechanism for recurrence in this setting is not clear.[113] On study, in contrast to most others, found that the rate of recurrent disease in NPHS2-associated disease was similar to those with idiopathic FSGS.[117]

There may be a rough correlation between genotype and severity of phenotype. Patients with frameshift or nonsense mutations in both alleles appear to have the most aggressive course. Patients with other variant alleles, particularly R229Q, tend to have later onset disease.[111] This particular podocin variant, R229Q, is present in 7% of most populations (allele frequency 3.5%) and appears to cause SRN when inherited together with another, more deleterious allele. It appears that the R229Q change leads to a partial loss of function and altered association with nephrin. In the heterozygous state, the presence of a R229Q variant appears to increase the risk of microalbuminuria.[118]

Genetic data supports the biochemical evidence of a podocin/nephrin interaction. Human genetic data suggests that the presence of a single NPHS2 mutation may increase the severity of NPHS1-associated CNS.[83] This is consistent with mouse genetic data suggesting that heterozygous defects in multiple podocyte genes can act together to produce a disease phenotype.[45]

In contrast to the typical nephrotic syndrome of in childhood, patients with two mutant NPHS2 alleles do not respond to steroid therapy.[114] There is no clear difference in clinical or pathological phenotype between podocin-mediated disease and “idiopathic” FSGS. Renal biopsies show minimal change disease or FSGS.[119] Given the adverse effects of prolonged steroid treatment, particularly in children, a strong case can be made for performing genetic testing for NPHS2 mutations soon after disease presentation to help assess the risk that steroid therapy will fail. Logistically, this is not yet straightforward to do in the clinic.

The variability in disease severity from person to person suggests that other factors (genetic and non genetic) are important in modulating this disease. It is not clear how much of this variability derives from differences in the specific NPHS2 defects. Studies in a mouse model of podocin-associated SRN suggests that strain-specific differences can have a significant effect on the phenotype.[120] It is likely that in humans, other genes similarly modify this disease.

Some studies have suggested that, similar to a large number of disease-associated membrane proteins, many podocin muta-tions lead to defective protein processing, folding, and/or localization, rather than an intrinsic defect in function. [121] [122] In addition, podocin defects alter the processing and localization of nephrin.[123] As with other membrane proteins, this has sparked interest in the possibility of using chaperone therapies to help correct the cellular defect.


CD2AP was initially identified as a T-cell adaptor protein.[59] Subsequent work showed that CD2AP localizes to the slit diaphragm, interacts with nephrin, and, when absent, causes nephrotic syndrome in mice. [25] [124] Further study showed that mice with one defective CD2AP allele have increased susceptibility to glomerular damage.[125] In humans, rare splice mutations have been identified in FSGS patients.[125] Studies in animal and cell models have suggested roles for CD2AP in slit diaphragm signaling and possible involvement in podocyte endocytosis. [126] [127] Mice heterozygous for CD2AP deficiency show increased accumulation of immunoglobins in the GBM, suggesting a possible role for CD2AP in targeting proteins for degradation.[125] CD2AP associates with podocyte actin, in particular the dynamic actin in endosomes. [128] [129] [130] Mice heterozygous for CD2AP deficiency show increased susceptibility to FSGS when crossed with mice with other podocyte defects.[45] The role of CD2AP variants in human sporadic and familial disease has not yet been extensively evaluated.


TRPC6 is a member of a large family of ion channels, the transient receptor potential family. TRPC6 (for transient receptor potential canonical 6), is a non-selective cation channel. TRPC6 is activated by diacylglycerol in a protein kinase C independent manner.[131] A TRPC6 mutation was found to be responsible for FSGS in a large New Zealand kindred.[132] This P112Q substitution was found to increase channel activity. Several additional mutations have now been reported.[55] In all reported families, disease follows autosomal dominant inheritance. Affected individuals typically present with adult-onset proteinuria in their third or fourth decade of life. Approximately 60% of patients with FSGS-associated TRPC6 mutations develop ESRD. Some, but not all, of the identified mutations increase TRPC6 activity in heterologous expression assays. TRPC6 localizes to the slit diaphragm and interacts directly with podocin and nephrin.[55] Although TRPC6 is a widely expressed protein, this form of disease appears to be limited to the kidney. Disease associated with TRPC6 mutations is similar clinically to ACTN4-associated disease, with kidney disease presenting in adolescence or adulthood. The variable expressivity of TRPC6 mutations suggests that other factors, genetic or environmental, are required for full expression of the phenotype. Mice with TRPC6 deleted show increased vascular smooth muscle contractility but no overt renal phenotype, consistent with the notion that human disease-associated mutations cause kidney disease via a gain-of-function mechanism.[133] Surprisingly, the induction of wild-type TRPC6 channels is associated with the development of a subset of acquired proteinuric diseases.[133a] This is an example where genetic disease of the glomerulus (TRPC6 mutations) and acquired forms of proteinuric diseases (TRPC6 induction) may share common downstream effectors in the development of renal dysfunction.



Mutations in the α-actinin-4 gene ACTN4 cause a form of kidney disease characterized by sub-nephrotic proteinuria, the development of podocyte degeneration, and FSGS. [135] [136] To date, five disease-causing mutations have been identified, all point mutations within the actin-binding domain of this protein. α-Actinin-4 is a widely expressed 100 kD homodimeric protein that bundles and crosslinks filamentous actin. Although widely expressed, its primary intrarenal localization is within the podocyte processes. α-Actinin-4 also interacts with a large number of other proteins, including beta-integrins, cell-adhesion molecules, and signaling proteins.[47] ACTN4 mediated disease is transmitted in an autosomal dominant manner. Affected individuals have one mutant ACTN4 allele. In addition to increased affinity to F-actin, mutant α-actinin-4 is more rapidly degraded than the wild-type protein. Thus the mechanism of disease may be a combination of loss-of-function and gain-of-function effects.[136]

Mice with a targeted deletion of the Actn4 gene develop glomerular disease, confirming an essential and non-redundant role for α-actinin-4 in the glomerulus.[137] Transgenic mice expressing mutant α-actinin-4 in podocytes support a biologically dominant effect of human mutations. [139] [140] As disease-associated ACTN4 mutants increase the affinity of the encoded protein to actin, a biologically dominant perturbation in podocyte mechanics may be an important part of the disease mechanism. [135] [136] The phenotype of this form of disease is late onset. Affected individuals do not develop nephrotic range proteinuria or the nephrotic syndrome. Although data is limited, it appears that this form of FSGS does not recur in kidneys transplanted into these patients.

Other Forms of Disease

Recently, mutations in the phospholipase C epsilon gene PLCE1 were shown to cause a recessive, early onset form of nephrotic syndrome with FSGS and/or diffuse mesangial sclerosis. Phospholipase C epsilon is expressed in both developing and developed podocytes. The mechanism of disease is not yet clear. Of particular interest is the observation that two children with PLCE1-mediated disease responded to immunosuppresive therapy.[139a]

Ruf and colleagues recently identified a locus on chromosome 2 that contains a gene responsible for steroid-sensitive nephrotic syndrome in a consanguineous family.[140] They also show that this locus is not responsible for disease in all steroid-sensitive nephrotic syndrome families, demonstrating that, like steroid-resistant disease, this phenotype is also genetically heterogeneous.

Syndromic Disease

Podocyte dysfunction is also seen as a component of several inherited multi-organ syndromes. These include disorders in which the podocytopathy has been well studies, and other disorders in which the nature and mechanism of the kidney lesion is obscure.


Individuals with Nail-Patella syndrome (NPS) display dysplastic nails, hypoplastic patellae, and glomerular disease characterized by hematuria and proteinuria.[141] This disorder follows autosomal dominant inheritance. Affected patients show a highly variable renal phenotype. An altered GBM is a characteristic pathologic finding, and may be associated with frank nephrosis. NPS is caused by mutations in the lmx1b transcription factor. [144] [145] [146]Lmx1b binds to the podocin promoter and appears to be critical to the transcription of a number of critical podocyte genes as well as genes encoding matrix proteins. [147] [148] [149] Mice with targeted deletion of the lmx1b gene display a phenotype similar to the human disease.[144] Expression studies suggest that the disease is caused by lmx1b haploinsufficiency, rather than a biologically dominant effect of mutant lmx1b.[148]


The WT1 transcription factor was cloned using positional methods on the basis of its role in the inheritance of Wilms tumor. [151] [152] WT1 has been extensively studied. Precise regulation of WT1 expression appears critical for kidney development as well as regulation of podocyte gene expression. [153] [154] [155]

Frasier syndrome and Denys-Drash syndrome (DDS) are related disorders both caused by WT1 mutations. [156] [157] [158] [159] These syndromes are characterized by glomerular disease as well as urogenital anomalies. Frasier syndrome is defined clinically by the presence of FSGS together with male pseudohermaphroditism and a high risk of gonadoblastoma. Control of alternative splicing of WT1, specifically the inclusion or omission of a three amino acid (KTS) region, appears critical for normal glomerulogenesis and sex determination. Mice lacking the KTS-containing isoform show complete XY sex reversal. [160] [161] WT1 splice mutations that alter the regulation of the splicing of this KTS region cause Frasier syndrome.[157] XY individuals with such mutations may appear as phenotypic females, whereas XX individuals with the same mutations can present with isolated glomerular disease. [162] [163] Denys-Drash syndrome is defined by diffuse mesangial sclerosis, genitourinary tumors, and pseudohermaphroditism and is most commonly caused by mutations in exon 9 of WT1. It is probably best to regard Frasier and DDS as parts of a spectrum of disorders resulting from WT1 mutations. Although most reported mutations associated with DDS are missense point mutations, there is overlap in the spectrum of mutations associated with these disorders.

Recently, several non-coding variants (SNPs) in the closely linked WT1 and WIT1 (Wilms tumor upstream neighbor 1) genes were genotyped in African Americans with and without FSGS.[162] This study found a significant association between specific haplotypes in the WT1/WIT1 gene locus and the risk of FSGS in this population.

Pierson Syndrome

Defects in the laminin-β2 gene LAMB2 cause Pierson syndrome.[163] In addition to congenital nephrosis, affected neonates display a number of ocular abnormalities that typically include microcoria, extreme non-reactive narrowing of the pupils. Pierson syndrome is recessive. Affected neonates are homozygous or compound heterozygous for defects in LAMB2. Defects in LAMB2 can also cause congenital nephrosis with minimal eye abnormalities.[164] In addition to podocyte abnormalities, mesangial sclerosis is a frequent histologic feature. Mice deficient in Lamb2 show marked proteinuria before the onset of overt podocyte abnormalities, demonstrating the importance of glomerular basement membrane components as a barrier to protein filtration.[165] As with NPHS1-associated congenital nephrotic syndrome, features of antenatal nephrosis can be detected by ultrasonography.[166]

Immunoosseous Dysplasia

Immunoosseous dysplasia is caused by mutations in the SMARCAL1 gene. [169] [170] This rare autosomal recessive disorder presents with spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. The renal lesion has not been extensively characterized, but chronic kidney disease, FSGS, and proteinuria appear to be common features. SMARCAL1 encodes a widely expressed protein involved in chromatin remodeling.


A recent report described a pair of siblings with end-stage kidney disease, epidermolysis bullosa, and deafness in association with homozygosity for frameshift mutations in the CD151 gene.[169] CD151 is a member of the tetraspanin family of cell surface proteins. CD151 interacts with ab-integrins to facilitate laminin binding.[170] Mice deficient in Cd151 develop proteinuria, FSGS, and kidney failure.[171]

Fabry Disease

Podocyte dysfunction is a typical component of Fabry disease, an X-linked deficiency in gene encoding α-galactosidase A.[172] Accumulation of the sphingolipid globotriaosylceramide is observed throughout the vasculature endothelium of affected patients as well as in podocytes and tubular epithelium. Some genetic variants may favor podocyte sphingolipid accumulation compared with other target tissues.[173] Nephrotic range proteinuria and podocyte foot process effacement are common feature of the nephropathy seen in Fabry disease.[174] Enzyme replacement therapy appears effective in reducing the glomerular sphingolipid deposits.[175]

Mitochondrial Disease

Mitochondrial disease can present with podocyte abnormalities.[176] The mitochondrial genome is a small circular extrachromosomal genome that is inherited maternally. A number of reports have documented mutations in the tRNA(Leu(URR)) gene associated with podocyte abnormalities as well as vari-ous non-glomerular phenotypes. [179] [180] [181] [182] A recent case report described a girl with FSGS in association with a mutation in the mitochondrial tRNA(Tyr) gene.[181] Even more recently, three infants were described who displayed with nephrosis in association with a mitochondrial RC complex II+V deficiency.[182]

Animal Models

Several animal models that show podocyte abnormalities and significant proteinuria have been described. Although several genetically engineered mice have been generated with defects in human disease genes to help understand the biology of disease, defects in several genes without known involvement in human disease have been shown to cause podocyte disease in animal models. FAT1 deficient mice show a congenital nephrotic phenotype similar to nephrin deficiency.[183] Mice lacking the nephrin interacting protein NEPH-1 show a similar phenotype.[90] A number of other spontaneous or genetically engineered mice show evidence of podocyte foot process effacement, proteinuria, and/or FSGS. Mice with a disrupted mpv17 gene, which encodes a peroxisomal protein that regulates MMP production, develop an FSGS-like lesion.[184] Mice deficient in RhoGDIa, a regulator of Rho activity, display massive proteinuria.[185] Mice homozygous for an ENU-induced mutation in the kreisler gene, encoding a leucine zipper transcription factor, demonstrate proteinuria and podocyte foot process effacement.[186] This growing list of rodent models will inform studies of human disease. However, most of these genes have not been directly implicated in human podocytopathies.

Genetic Heterogeneity/Other Loci

The known NS/FSGS genes do not account for all inherited forms of these diseases. Mutations in the NPHS2, NPHS1, ACTN4, CD2AP, TRPC6 genes account for only a fraction of familial disease presenting after infancy. It is not clear what percentage of “sporadic” or “idiopathic” NS or FSGS reflect the effects of underlying gene defects. It seems likely that in addition to other Mendelian forms of disease (in which very rare mutations cause a markedly increased disease risk), a number of genetic variants will be identified that modestly increase the risk of disease, but are not sufficient to cause disease. The approximately fourfold increased risk of FSGS in individuals of African descent is likely the result of such variants.

Podocyte Protein Expression in Secondary Disease

A number of studies have looked at changes in the expression of disease-causing genes and the encoded proteins in sporadic and secondary forms of disease. [189] [190] [191] [192] [193] [194] [195] Down regulation of nephrin protein has been reported in a variety of rodent glomerular injury models as well as in human glomerulopathies, including diabetic nephropathy. [196] [197] This loss of nephrin appears to occur at the protein rather than the transcriptional level, as changes in nephrin mRNA levels has been reported to be increased or unchanged in many of these disease states. In some rodent models, treatment with angiotensin-converting enzyme inhibitors has been reported to correct the decrease in nephrin expression. [198] [199] Podocin levels appear to decrease in pediatric nephrotic syndrome, as does nephrin expression.[187] An increased in podocyte gene transcript levels together with decrease in protein expression has been observed for several different podocyte markers.[198] Glomerular α-actinin-4 protein has been reported to be increased in membranous glomerulopathy but decreased in minimal change disease.[199] It remains difficult to know what changes in expression are involved in pathogenesis of disease, rather than a response to disease.

Genetics of Secondary Disease

What role does variation in podocyte genes play in secondary forms of kidney disease? Do different nephrin, CD2AP, or podocin haplotypes confer different susceptibilities to glomerulopathy in response to, say, obesity, diabetes, hypertension, or HIV infection? These issues have not been extensively studied to date. Although, as described earlier, some variants in NPHS1 and NPHS2 may convey increased susceptibility to podocyte injury, studies to date have not suggested a major role for these genes in common forms of nephropathy. As we gain increasing understanding of the genes responsible for podocyte and slit diaphragm function, as well as improved technology for examining large numbers of genetic variants, we will be better able to assess the role of podocyte genetics in common forms of chronic renal injury.

Genetic Testing

Genetic testing in the evaluation and management of patients with FSGS or NS (or both) is not yet a routine part of clinical care. A reasonable argument can be made for testing children with nephrotic syndrome for NPHS2 mutations, at least if response to initial steroid therapy seems minimal. It appears clear that NPHS2-mediated disease does not respond to immunosuppression. Thus early diagnosis could spare children from the adverse effects of prolonged immunosuppressive therapy. Mutations in ACTN4, TRPC6, and CD2AP are very rare causes of disease and it is difficult to argue that analysis of these genes should be a routine part of the evaluation of a proteinuric patients. However, when evaluating a patient with end-stage renal disease secondary to FSGS or NS for kidney transplant, physicians should be aware of the frequently familial nature of these diseases. Particular care should be taken not to transplant a living kidney from a pre-symptomatic but genetically affected family member. At present, one commercial company as well as several research laboratories perform genetic analysis of NPHS2 and other NS/FSGS genes.

As noted earlier, prenatal genetic testing for NPHS1 mutations is now routine in pregnancies in at-risk couples. This is straightforward in Finland where two mutations account for 95% of disease, but more involved in other locales.


Individuals with FSGS or NS as a result of mutations in the known disease-causing podocyte genes are resistant to immunosuppressive therapy. It has been clearly shown that children with podocin-mutant disease do not respond to glucocorticoids.[114] However, there have been families reported in which familial disease does respond to steroids; responsible genes have not been identified. [142] [202] Thus, a family history of NS/FSGS does not rule out the possibility that the disease in that family may be treatment responsive. It is increasingly clear that the inherited podocytopathies form a genetically heterogeneous group of disease, and it is likely that once more of the underlying genetic alterations are understood, we will be better able to predict response to therapy by genetic testing. At present, aggressive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (or both) appears to be the appropriate therapy for steroid-resistant inherited podocytopathies, although the data in support of this is purely conjectural and anecdotal.


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