Nephrology Dialysis Transplantation

NDT Advance Access originally published online on April 20, 2007
Nephrology Dialysis Transplantation 2007 22(7):1849-1852; doi:10.1093/ndt/gfm098

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Familial nephrotic syndrome: PLCE1 enters the fray^*

Jonathan Ashley Jefferson and Stuart J. Shankland

Division of Nephrology, University of Washington, Seattle, Washington, USA

Correspondence and offprint requests to: Stuart J. Shankland, MD, Head, Division of Nephrology, University of Washington, 1959 NE Pacific Street, Box 356521, Seattle, Washington 98195, USA. Email: stuartjs{at}u.washington.edu

Keywords: focal segmental glomerulosclerosis; genetic disorders; nephrotic syndrome; phospholipase C; podocyte

	Mutations in phospholipase C epsilon 1 gene cause early onset nephrotic syndrome

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
Marked advances in molecular biology are constantly enabling new insights into renal pathophysiology and the treatment of human disease. In the December 2006 issue of Nature Genetics, Hinkes et al. [1] describe a novel mechanism for early nephrotic syndrome in children due to mutations in PLCE1, a gene which encodes one of a family of phospholipase C enzymes (PLC1). Affected children develop proteinuria by four years of age, with renal pathology demonstrating diffuse mesangial sclerosis (truncating mutations) or focal segmental glomerulosclerosis (missense mutations). The majority progress to end-stage renal disease by 5 years of age; however, of particular interest is that two children, both with truncating mutations in PLCE1, responded to treatment with steroids and/or ciclosporin. This is the first time that an inherited childhood nephrotic syndrome has responded to therapy.

	Nephrotic syndrome and the glomerular filtration barrier: is the podocyte slit diaphragm the principal determinant?

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
Nephrotic syndrome occurs due to a breakdown in one or more layers of the glomerular filtration barrier. This barrier consists of three layers, the fenestrated glomerular endothelium, the glomerular basement membrane (GBM) and the slit diaphragm of the podocyte, each likely contributing to the charge and size selective properties. Debate continues over the exact contribution of each layer, but recent evidence has implicated the previously overlooked podocyte and its slit diaphragm as major contributing factors. The slit diaphragm lies between adjacent podocyte foot processes and consists of the structural transmembrane protein nephrin which forms heterodimers with NEPH-1 and NEPH-2 to bridge the slit pore (Figure 1). Nephrin is anchored to the podocyte membrane by podocin and CD2AP. Other structural proteins of the slit diaphragm complex include P-cadherin, FAT and ZO-1. The slit diaphragm functions to permit a high hydraulic flux, whilst limiting the passage of macromolecules such as albumin. In addition to this structural role, the slit diaphragm complex, in association with TRPC6 (an epithelial calcium channel), signals through a phosphoinositide 3-OH kinase dependent AKT pathway to modulate cellular processes such as actin cytoskeletal remodelling and cell survival [2,3]

View larger version (57K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. Podocyte slit diaphragm: The major molecules comprising the podocyte slit diaphragm are demonstrated. Signalling by PLC1 is also illustrated, but note this is limited to podocyte cell body and major processes and not foot processes.

 
Mechanisms that disrupt the slit diaphragm complex result in podocyte dysfunction and/or loss, leading in massive proteinuria. Mice with target deletions for nephrin [4], podocin [5], NEPH-1 [6], FAT [7] develop massive proteinuria, and antibodies to nephrin cause nephrotic syndrome, notably without foot process effacement [8]. Moreover, in human glomerulonephritides, such as diabetic nephropathy [9], membranous nephropathy [10] and minimal change disease [11], abnormalities in the expression and localization of certain slit diaphragm proteins have been described, which may resolve with successful treatment.

	Familial FSGS may be caused by inherited structural abnormalities in podocyte proteins

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
Families with steroid resistant nephrotic syndrome (SRNS) secondary to mutations in genes encoding podocyte structural proteins are now well recognized. The first to be recognized was NPHS1 (nephrin) mutations, causing congenital nephrotic syndrome of the Finnish type [12]. Mutations in the NPHS2 gene encoding podocin are the commonest cause of SRNS in children, accounting for some 30–46% of cases of familial SRNS and 11–19% of sporadic SRNS [13–15]. Congenital nephrotic syndrome secondary to diffuse mesangial sclerosis may also be caused by mutations in WT1 [16] and LAMB2 [17]. By contrast, in adults, NPHS2 (podocin) mutations are a rare cause of FSGS [18,19]. Familial FSGS has been described in adults, due to mutations in the genes encoding alpha actinin-4 [20] and TRPC6 [2,3].

	PLCE1 may play a critical role in glomerular development

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
Familial FSGS is typically due to mutations in genes encoding structural podocyte proteins; however, PLC is an enzyme. How might PLC mutations result in glomerular disease? Phospholipase C is a signalling protein for many G protein-coupled receptors, including angiotensin II, and promotes the downstream activation of protein kinase C and enhances calcium-signalling events. PLC1 has a widespread distribution, but within the kidney the PLC1 protein is enriched in glomeruli and localizes to the cytoplasm of the podocyte cell body and both major and intermediate processes. Studies in early kidney development demonstrated the appearance of PLC1 at the S-shaped stage, with high expression during early capillary loop stage [1]. It is suggested that the absence of PLC1 may halt kidney development at the capillary loop stage leading to the morphological phenotype of diffuse mesangial sclerosis. Of note, this is associated with a marked reduction in the expression of nephrin and podocin.

The role of PLC in renal pathophysiology remains complex however, as PLC1 knockout mice do not appear to exhibit a renal phenotype. In addition, enhanced (rather than diminished) signalling through a form of PLC within podocytes (using a mouse transgenic for Gq with nephrin promoter giving targeted podocyte expression of a constitutively active Gq) results in podocyte injury, proteinuria and reduced renal mass [21].

	Clinical applications

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
How can we translate the rapidly emerging data from molecular studies into clinical practice? At present, genetic screening in patients with nephrotic syndrome is mostly limited to mutations in NHPS1 (nephrin) and NPHS2 (podocin), but this will probably change dramatically with advances in gene sequencing.

Even today, the detection of NPHS2 (podocin) mutations in children with nephrotic syndrome greatly impacts clinical care. Children with homozygous mutations are known to be steroid- and cyclosporine-resistant, and this will allow these therapies, and their attendant side effects, to be avoided. FSGS commonly recurs post kidney transplant (30–40%). Fortunately, the incidence of post-transplant recurrent disease is much lower in patients with homozygous NPHS2 mutations (8%), although the choice of donor needs to be carefully considered, as the parents are obligate heterozygotes [22]. Interestingly, in patients with FSGS who are heterozygous for NPHS2 mutations, there seems to be a high incidence of recurrent disease (60%).

In childhood nephrotic syndrome secondary to mutations in PLCE1, the majority of children had a poor prognosis; however, two patients with truncating mutations are described who responded to therapy [1]. Although there are some reports of inherited glomerulopathies that are responsive to immunosuppression [23], this contrasts with the majority of inherited glomerulopathies that are resistant. It remains to be determined which specific factors are associated with an improved response and whether there is a time window, during which intervention may be successful. The application of this interesting work in decisions regarding renal transplantation will probably also unravel over time.

In summary, the podocyte is the cellular target in the majority of nephrotic disorders, whether this is due to genetic mutations (nephrin, podocin, TRPC6, PLC1, -actinin-4) or acquired disorders (Table 1). These multiple factors impact the onset and course of disease, treatment responses and options and the likelihood of transplant recurrence.

View this table: [in this window] [in a new window]   Table 1. Clinical disorders of the podocyte

 

	Acknowledgements

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 
This work was supported by National Institutes of Health grants to S.J.S. (DK60525, DK56799, DK 51096), and by the American Diabetes Association. S.J.S. is also an Established Investigator of the American Heart Association.

Conflict of interest statement. None declared.

	Notes

 
*Comment on Hinkes B, Wiggins RC, Gbadegesin R et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 2006; 38: 1397–1405.

	References

Top Mutations in phospholipase C... Nephrotic syndrome and the... Familial FSGS may be... PLCE1 may play a... Clinical applications Acknowledgements References

 

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Received for publication: 1. 2.07
Accepted in revised form: 5. 2.07

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