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Podocyte-Specific Gene Mutations Are Coming of Age

Academic Renal Unit, University of Bristol, Bristol, United Kingdom

Correspondence: Prof. Peter W. Mathieson, Academic Renal Unit, Southmead Hospital, Bristol BS10 5NB, United Kingdom. Phone/Fax: +44-0-117-959-5438; E-mail: p.mathieson{at}bristol.ac.uk

	Introduction

Top Introduction DISCLOSURES REFERENCES

 
Major leaps have been made recently in the understanding of the cause of proteinuria and hence in the regulation of glomerular permeability in health. Progress has been fueled by the description of single-gene mutations, the majority of which affect genes expressed selectively in the podocyte, resulting in nephrotic syndrome in human and mouse.¹ This has placed the podocyte center stage as a key regulator of normal selective permeability to albumin in the glomerular capillary wall, although we should not forget that single-gene mutations affecting components of the glomerular basement membrane can also result in heavy proteinuria,² or that the third component of the glomerular capillary wall, the glomerular endothelial cell, can also play an important role in regulating glomerular permeability in health and disease.³

The first podocyte-specific gene identified by studying disease-associated mutations was NPHS1, encoding nephrin⁴; this was swiftly followed by identification of NPHS2, encoding podocin,⁵ also a novel protein important in the structure and function of glomeruli.⁶ Since the discovery of nephrin and podocin, several other disease-associated podocyte-specific gene defects have been reported, and, undoubtedly, there will be more to come.

Mutations in different podocyte genes or different mutations in the same gene result in varying phenotypes regarding severity and age of onset of proteinuria, and it is clear that there are likely to be other disease-modifying genes or environmental influences. Moreover, congenital forms of nephrotic syndrome are rare, and a question that intrigues nephrologists and basic scientists alike is whether the more common forms of sporadic, often later onset nephrotic syndrome could also be associated with mutations or polymorphisms in podocyte-specific genes, as predisposing factors or contributors to a complex etiology involving genetic–environmental interactions. If so, then study of these genes could be clinically useful in diagnosis and prognosis, especially concerning the likelihood of corticosteroid responsiveness and the issue of likely recurrence in renal transplants for patients who progress to end-stage renal failure.

The article in this issue of JASN by Hinkes et al.,⁷ the product of an impressive multinational collaboration, sheds light on these issues. The study amassed 430 patients with steroid-resistant nephrotic syndrome, the vast majority of whom were the only affected family member, although the series did include 23 families with more than one affected member. The patients were screened for mutations in NPHS2 by direct sequencing of all eight exons of the gene. Eighty-two patients (19% of the total) had mutations in NPHS2. In the families with more than one affected member, the proportion with NPHS2 mutations rose to 39%. In patients with two NPHS2 mutations, the authors report that approximately 40% had one truncating (frameshift or nonsense) mutation and an additional 30% had homozygous R1308Q mutations (the "founder" NPHS2 mutation identified by Boute et al.⁵). These two groups of individuals nearly all developed nephrotic syndrome at an early age (<6 yr, with a mean age of onset <2 yr). The remaining 30% of patients with other mutations or variants in NPHS2 had later onset disease without any further specific link between any given genotype and age of onset (although the numbers of patients with each genotype were small). Mutation type did not affect rate of deterioration, time from onset to ESRD being the same in all groups.

Although this represents real progress, even within the groups with early presentation there was still a wide range of age of onset. Also, >80% of the collection with steroid-responsive nephrotic syndrome did not have any abnormality of NPHS2, so their proteinuria remains unexplained; clearly there is more work to be done.

The power of large multinational studies such as this one will be essential if analyses of genotype–phenotype relationships in nephrotic syndrome are to yield informative conclusions. Ideally, genetic analysis should be more widely available as a diagnostic and prognostic aid in patients presenting with nephrotic syndrome; however, at present, clinicians will need further guidance from geneticists about the interpretation of genotype–phenotype relationships. Hinkes et al. are to be congratulated for leading the way.

	DISCLOSURES

Top Introduction DISCLOSURES REFERENCES

 
None.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

See related article, "Specific Podocin Mutations Correlate with Age of Onset in Steroid-Resistant Nephrotic Syndrome," on pages 365–371.

	REFERENCES

Top Introduction DISCLOSURES REFERENCES

 

1. Tryggvason K, Patrakka J, Wartiovaara J: Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354 : 1387 –1401, 2006[Free Full Text]
2. Zenker M, Aigner T, Wendler O, Tralau T, Müntefering H, Fenski R, Pitz S, Schumacher V, Royer-Pokora B, Wühl E, Cochat P, Bouvier R, Kraus C, Mark K, Madlon H, Dötsch J, Rascher W, Maruniak-Chudek I, Lennert T, Neumann LM, Reis A: Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 13 : 2625 –2632, 2004[Abstract/Free Full Text]
3. Ballermann BJ: Contribution of the endothelium to the glomerular permselectivity barrier in health and disease. Nephron Physiol 106 : 19 –25, 2007[CrossRef]
4. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 4 : 575 –582, 1998
5. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24 : 349 –354, 2000[CrossRef][Medline]
6. Huber TB, Schermer B, Benzing T: Podocin organizes ion channel-lipid supercomplexes: Implications for mechanosensation at the slit diaphragm. Nephron Exp Nephrol 106 : e27 –e31, 2007[CrossRef][Medline]
7. Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, Hasselbacher K, Ozaltin F, Hildebrandt F, members of the APN Study Group: Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19 : 365 –371, 2008[Abstract/Free Full Text]

This Article Full Text (PDF) All Versions of this Article: ASN.2007121341v1 19/2/190    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mathieson, P. W. Search for Related Content PubMed PubMed Citation Articles by Mathieson, P. W. Related Collections Related Article