Abstract
Background
The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity.
Case-Diagnosis/Treatment
A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS.
Conclusions
This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.
This is a preview of subscription content, log in via an institution to check access.
References
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
Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:e907–e919
Santin S, Bullich G, Tazon-Vega B, Garcia-Maset R, Gimenez I, Silva I, Ruiz P, Ballarin J, Torra R, Ars E (2011) Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6:1139–1148
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
Benoit G, Machuca E, Antignac C (2010) Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 25:1621–1632
Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, Hasselbacher K, Ozaltin F, Hildebrandt F (2008) Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:365–371
Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 110:1659–1666
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
Machuca E, Hummel A, Nevo F, Dantal J, Martinez F, Al-Sabban E, Baudouin V, Abel L, Grunfeld JP, Antignac C (2009) Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney Int 75:727–735
Kottgen A, Hsu CC, Coresh J, Shuldiner AR, Berthier-Schaad Y, Gambhir TR, Smith MW, Boerwinkle E, Kao WH (2008) The association of podocin R229Q polymorphism with increased albuminuria or reduced estimated GFR in a large population-based sample of US adults. Am J Kidney Dis 52:868–875
Reiterova J, Safrankova H, Obeidova L, Stekrova J, Maixnerova D, Merta M, Tesar V (2012) Mutational analysis of the NPHS2 gene in Czech patients with idiopathic nephrotic syndrome. Folia Biol (Praha) 58:64–68
Russell-Eggitt I, Bockenhauer D (2013) The blind kidney: disorders affecting kidneys and eyes. Pediatr Nephrol. doi:10.1007/s00467-012-2404-5
Bower M, Salomon R, Allanson J, Antignac C, Benedicenti F, Benetti E, Binenbaum G, Jensen UB, Cochat P, DeCramer S, Dixon J, Drouin R, Falk MJ, Feret H, Gise R, Hunter A, Johnson K, Kumar R, Lavocat MP, Martin L, Moriniere V, Mowat D, Murer L, Nguyen HT, Peretz-Amit G, Pierce E, Place E, Rodig N, Salerno A, Sastry S, Sato T, Sayer JA, Schaafsma GC, Shoemaker L, Stockton DW, Tan WH, Tenconi R, Vanhille P, Vats A, Wang X, Warman B, Weleber RG, White SM, Wilson-Brackett C, Zand DJ, Eccles M, Schimmenti LA, Heidet L (2012) Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat 33:457–466
Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT (2011) LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat 32:557–563
Bockenhauer D, Medlar AJ, Ashton E, Kleta R, Lench N (2012) Genetic testing in renal disease. Pediatr Nephrol 27:873–883
Acknowledgments
We thank Corinne Antignac and Laurence Heidet for the discussion of the manuscript, Mária Bernáth and Gábor Nyírő for their technical assistance. This work was supported by Pfizer, TÁMOP-4.2.1/B-09/1/KMR-2010-0001 and János Bolyai Scholarship (KT).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kerti, A., Csohány, R., Wagner, L. et al. NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis. Pediatr Nephrol 28, 2061–2064 (2013). https://doi.org/10.1007/s00467-013-2542-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-013-2542-4