Nephrotic syndrome is a pathologic entity characterized by massive loss of protein in the urine, hypoalbuminemia, and edema. It constitutes one of the most common diagnoses made in pediatric nephrology (1). About 90% of all children with sporadic nephrotic syndrome, meaning nephrotic syndrome not associated with a positive family history, respond to steroid treatment (2). Unfortunately, the remaining steroid-resistant patients are at high risk for adverse effects of the required invasive drug therapy and prone to develop progressive disease, and renal failure. End-stage renal disease, requiring dialysis or transplantation therapy, occurs in a large number of these patients which places an enormous burden on these children and poses a huge challenge for the caring physicians and families (3). Thus, it comes as no surprise that the recent identification of genes involved in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) has generated a great deal of interest. It is now clear that mutations in genes encoding for proteins of the podocyte, the visceral epithelial cell of the kidney glomerulus, can cause nephrotic syndrome (4). NPHS1, encoding the podocyte protein nephrin, has been identified as the responsible gene in congenital nephrotic syndrome of the Finnish type (5). Podocin (6), α-actinin-4 (7), TRPC6 (8,9), and CD2AP (10) are all components of the podocyte foot processes that have been discovered subsequently through genetic approaches. Mutations in these genes cause focal-segmental glomerulosclerosis and proteinuria resistant to the treatment with corticosteroids. In fact, it is now getting clear that a majority of SRNS cases may have a genetic basis. I.e., mutations in the podocin-coding gene NPHS2 account for about 20% of cases with sporadic SRNS (11–14).
Mutations in the Wilms' tumor predisposing gene WT1 now join NPHS2 as an important gene involved in the pathogenesis of sporadic SRNS. The study by Mucha and the APN investigators in this issue together with previous work from the same investigators shows that mutations in WT1 account for sporadic SRNS in almost 10% of cases (15,16). WT1, the first gene found to be inactivated in Wilms' tumor, or nephroblastoma (17) encodes a zinc finger transcription factor that functions both as tumor suppressor (18) and as critical regulator of kidney and gonad development (19). This protein is expressed in a tightly regulated pattern within the embryonic kidney and is essential for renal development in mice (20). Germline deletions or mutations of WT1 have been linked to WAGR (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation) syndrome (21,22), Drash syndrome (23) and Frasier syndrome (24). Mucha et al. now show that WT1 mutations also have to be considered in patients with sporadic, nonsyndromic SRNS (15). All mutations in this study localized to exons 8 and 9 of WT1 and patients with WT1-associated SRNS predominantly displayed primary focal and segmental glomerulosclerosis on kidney biopsy.
This study has important implications: The authors clearly show in a large cohort of SRNS patients that dominant de novo mutations of WT1 account for a considerable number of SRNS cases in phenotypically female patients. Since these mutations can be associated with genitourinary malformations, male pseudohermaphroditism and tumorigenesis in offspring of these patients testing for WT1 mutations should be included in the genetic work up and is required for genetic counseling. Pathogenic mutations exclusively localized to exons 8 and 9 of the WT1 gene. Although intronic mutations could not be excluded in this study, these data indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS may be sufficient. Taken together, these data suggest that, in addition to screening all SRNS patients for NPHS2 mutations, phenotypically female SRNS patients or male SRNS patients with genitourinary abnormalities should be readily screened for mutations in WT1 exons 8 and 9.
The past several years have witnessed important advances in understanding the molecular basis of nephrotic syndrome and the importance of the glomerular podocyte for the function of the glomerular filter of the kidney (25,26). The recent emergence of the podocyte as the culprit in nephrotic syndrome has raised new hope for developing rational treatment strategies and provided novel diagnostic tools for the screening of SRNS-associated gene mutations (27,28). This rapidly increasing knowledge about the molecular genetics of nephrotic syndrome will not only help to identify novel therapeutic targets for patients with nephrotic syndrome but will soon allow predictions about whether a child will respond to invasive treatment strategies. Therefore, genetic testing is mandatory in all children with SRNS and has a huge promise for the future. Genetic testing comes of age: future is now.
References
Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, Kausz AT, Eknoyan G, Levey AS 2003 National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 111: 1416–1421
Niaudet P, Broyer M 2000 Management of steroid-responsive nephrotic syndrome. Pediatr Nephrol. 14: 770–771
Niaudet P 2004 Podocin and nephrotic syndrome: implications for the clinician. J Am Soc Nephrol. 15: 832–834
Niaudet P 2004 Genetic forms of nephrotic syndrome. Pediatr Nephrol. 19: 1313–1318
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 1998 Positionally cloned gene for a novel glomerular protein-nephrin-is mutated in congenital nephrotic syndrome. Mol Cell. 1: 575–582
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C 2000 NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 24: 349–354 Erratum in: Nat Genet25:125–
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR 2000 Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 24: 251–256
Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR 2005 TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 37: 739–744
Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB 2005 A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 308: 1801–1804
Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS 2003 CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science. 300: 1298–1300
Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C 2004 NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int. 66: 571–579
Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A 2002 Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 13: 388–393
Frishberg Y, Rinat C, Megged O, Shapira E, Feinstein S, Raas-Rothschild A 2002 Mutations in NPHS2 encoding podocin are a prevalent cause of steroid-resistant nephrotic syndrome among Israeli-Arab children. J Am Soc Nephrol. 13: 400–405
Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F 2004 Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol. 15: 722–732
Mucha B, Ozaltin F, Hinkes BG, Hasselbacher K, Ruf RG, Schultheiss M, Hangan D, Hoskins B, Schulze Everding A, Bogdanovic R, Seeman T, Hoppe B, Hildebrandt F, Group MotAS 2005 Mutations in the Wilms' Tumor 1 Gene Cause Isolated Steroid Resistant Nephrotic Syndrome and Occured in Exons 8 and 9. Pediatr Res. 59: XXX
Ruf RG, Schultheiss M, Lichtenberger A, Karle SM, Zalewski I, Mucha B, Everding AS, Neuhaus T, Patzer L, Plank C, Haas JP, Ozaltin F, Imm A, Fuchshuber A, Bakkaloglu A, Hildebrandt F 2004 Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int. 66: 564–570
Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR 1990 Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor. Science. 250: 991–994
Rivera MN, Haber DA 2005 Wilms tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer. 5: 699–712 Erratum in: Nat Rev Cancer 2005. 5:835–
Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D, van Heyningen V, Hastie N 1990 The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 346: 194–197
Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R 1993 WT-1 is required for early kidney development. Cell. 74: 679–691
Miller RW, Fraumeni JF Jr Manning MD 1964 Association of Wilms's tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med. 270: 922–927
Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, et al. 1990 Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 60: 509–520
Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, et al. 1991 Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 67: 437–447
Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K 1997 Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 17: 467–470
Mundel P, Shankland SJ 2002 Podocyte biology and response to injury. J Am Soc Nephrol. 13: 3005–3015
Kerjaschki D 2001 Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest. 108: 1583–1587
Benzing T 2004 Signaling at the slit diaphragm. J Am Soc Nephrol. 15: 1382–1391
Huber TB, Benzing T 2005 The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 14: 211–216
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Benzing, T. Genetic Testing Comes of Age: WT1 Mutations in Steroid-Resistant Nephrotic Syndrome: Commentary on the article by Mucha et al. on page 325. Pediatr Res 59, 165–166 (2006). https://doi.org/10.1203/01.pdr.0000202150.71520.9e
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1203/01.pdr.0000202150.71520.9e
This article is cited by
-
Complete remission of nephrotic syndrome in an infant with focal segmental glomerulosclerosis: is it renin–angiotensin blockade?
Pediatric Nephrology (2009)
-
Renin-angiotensin axis blockade reduces proteinuria in presymptomatic patients with familial FSGS
Pediatric Nephrology (2007)
-
Therapie der fokal segmentalen Glomerulosklerose
Der Nephrologe (2006)