1 Department of Child Health, Faculty of Medicine, Universitas Padjadjaran Bandung, Bandung, Indonesia. 2 Medical Faculty, Health Research Unit, Universitas Padjadjaran Bandung, Bandung, Indonesia. 3 Department of Pediatrics, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Objective: Although several NPHS2 gene mutations and polymorphisms were described and associated with clinical manifestation of steroid-resistant nephrotic syndrome (SRNS), the occurrence of these genetic abnormalities or variants appeared to be influenced by race and ethnic group. We have investigated probable mutations and variants in NPHS2 gene involved in SRNS and their association with clinical manifestations. Methods: We examined 28 children with primary SRNS whovisited the pediatric nephrology division of 10 teaching hospitals in Indonesia. Molecular genetic studies of the NPHS2 gene were conducted through screenings for the exon 1, exon 2, and exon 8. The mutational analysis of NPHS2 was performed by DNA sequencing. Fisher’s Exact Test was used to determine the correlation between NPHS2 polymorphisms and clinical manifestations.Results: Seven females (25%) and 21 males (75%) participated in the study. The mean age of the subjects with 95% CI is: 7.6 (6.1 - 9.0) years while the mean age at onset of disease with 95% CI is: 5.4 (3.9 - 7.0) years. Sixteen patients (57.14%) were younger than 6 years at the onset of disease. Seventeen (60.7%) subjects had normal eGFR, while 11 (39.3%) had chronic renal insufficiency. The mean eGFR of the subjects with 95% CI is: 111.4 (87.7 - 135.1) ml/min/1.73 m2. The mean systolic blood pressure with 95% CI is: 117.0 (108.9 - 125.1) mmHg and the mean diastolic blood pressure with 95% CI is: 77.0 (70.3 - 83.7) mmHg. We identified 6 NPHS2polymorphisms, i.e. g.-52G>T, c.101A>G, g.-117C>T, c.288C>T, c.954C>T, and c.1038A>G and no mutation was found. There was no correlation between NPHS2 polymorphisms and clinical manifestations (p > 0.05). Conclusion: The results demonstrate no mutation of NPHS2 gene, and the 6 NPHS2 gene polymorphisms that were identified have no correlation with the clinical manifestation in Indonesian children with SRNS.
Rachmadi, D. , Melani, A. and Monnens, L. (2015) NPHS2 Gene Mutation and Polymorphisms in Indonesian Children with Steroid-Resistant Nephrotic Syndrome. Open Journal of Pediatrics, 5, 27-33. doi: 10.4236/ojped.2015.51006.
[1] Clark, A.G. and Barrat, T.M. (1999) Steroid Responsive Neprotic Syndrome. In: Barrat, T.M., Avner, E.D. and Harmon, W.E., Eds., Pediatric Nephrology, 4th Edition, Lippincott Willams & Wilkins, Baltimore, 73l-747. [2] Fydryk, J. and Querfeld, U. (2002) The Nephrotic Syndrome-Idiopathic Steroid Resistant Nephrotic Syndrome. In: Cochat, P., Ed., European Society for Paediatric Nephrology Handbook, ESPN, Switzerland, 259-262. [3] Roth, K.S., Amaker, B.H. and Chan, J.C.M. (2002) Nephrotic Syndrome: Pathogenesis and Management. Pediatrics in Review, 23, 237-247. http://dx.doi.org/10.1542/pir.23-7-237 [4] Hogg, R.J., Portman, R.J., Milliner, D., Lemley, K.D., Eddy, A. and Ingelfinger, J. (2000) Evaluation and Management of Proteinuria and Nephrotic Syndrome in Children: Recommendations from a Pediatric Nephrology Panel Established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE). Pediatrics, 105, 1242-1249.
http://dx.doi.org/10.1542/peds.105.6.1242 [5] Kitamura, A., Tsukaguchi, H., Iijima, K., Araki, J., Hattori, M., Ikeda, M., et al. (2006) Genetics and Clinical Features of 15 Asian Families with Steroid-Resistant Nephrotic Syndrome. HealthNephrology Dialysis Transplantation, 21, 3133-3138. http://dx.doi.org/10.1093/ndt/gfl347 [6] Caridi, G., Perfumo, F. and Ghiggeri, G.M. (2005) NPHS2 (Podocin) Mutations in Nephrotic Syndrome. Clinical Spectrum and Fine Mechanisms. Pediatric Research, 57, 54R-61R.
http://dx.doi.org/10.1203/01.PDR.0000160446.01907.B1 [7] Niaudet, P. (2004) Genetic Form of Nephrotic Syndrome. Pediatric Nephrology, 19, 1313-1318.
http://dx.doi.org/10.1007/s00467-004-1676-9 [8] Bagga, A. and Mantan, M. (2005) Nephrotic Syndrome in Children. Indian Journal of Medical Research, 122, 13-28. [9] Antignac, C. (2002) Genetic Models: Clues for Understanding the Pathogenesis of Idiopathic Nephrotic Syndrome. Journal of Clinical Investigation, 109, 447-449. http://dx.doi.org/10.1172/JCI0215094 [10] Franceschini, N., Karl, N., Jeffrey, K., Louise, M. and Cheryl, W. (2006) NPHS2 Gene, Nephrotic Syndrome and Focal Segmental Glomerulosclerosis: A HuGE Review. Genetics in Medicine, 8, 63-75.
http://dx.doi.org/10.1097/01.gim.0000200947.09626.1c [11] International Study of Kidney Disease in Children (ISKDC) (1981) The Primary Nephrotic Syndrome in Children. Identification of Patients with Minimal Change Nephrotic Syndrome from Initial Response to Prednison. The Journal of Pediatrics, 98, 561-564. http://dx.doi.org/10.1016/S0022-3476(81)80760-3 [12] Hinkes, B., Vlangos, C., Heeringa, S., Mucha, B., Gbadegesin, R., Liu, J., et al. (2008) Specific Podocin Mutations Correlate with Age of Onset in Steroid-Resistant Nephrotic Syndrome. Journal of the American Society of Nephrology, 19, 365-371. http://dx.doi.org/10.1681/ASN.2007040452 [13] Weber, S., Gribouval, O., Esquivel, E.L., Moriniere, V., Tête, M.J., Legendre, C., et al. (2004) NPHS2 Mutation Analysis Show Genetic Heterogeneity of Steroid-Resistant Nephrotic Syndrom and Lowpost-Transplant Recurrence. Kidney International, 66, 571-579.
http://dx.doi.org/10.1111/j.1523-1755.2004.00776.x [14] Caridi, C., Berteli, R., Carrea, A., Di Duca, M., Catarsi, P., Artero, M., et al. (2001) Prevalence, Genetics, and Clinical Features of Patients Carrying Podocin Mutations in Steroid-Resistant Nonfamilial Focal Segmental Glomerulosclerosis. Journal of the American Society of Nephrology, 12, 2742-2746. [15] Karle, S., Uetz, B., Ronner, V., Glaeser, L., Hildebrandt, F. and Fuchshuber, A., Members of the APN Study Group (2002) Novel Mutations in NPHS2 Are Detected in Familial as Well as Sporadic Steroid Resistant Nephritic Syndrome. Journal of the American Society of Nephrology, 13, 388-393. [16] Caridi, G., Bertelli, R., Di Duca, M., Dagnino, M., Emma, F. and Muda, A.O. (2003) Broadening the Spectrum of Diseases Related to Podocin Mutations. Journal of the American Society of Nephrology, 14, 1278-1286. http://dx.doi.org/10.1097/01.ASN.0000060578.79050.E0 [17] Ruf, R.G., Lichtenberger, A., Karle, S.M., Haas, J.P., Anacleto, F.E., Schultheiss, M., et al., The APN Study Group (2004) Patients with Mutations in NPHS2 (Podocin) Do Not Respond to Standard Steroid Treatment of Nephrotic Syndrome. Journal of the American Society of Nephrology, 15, 722-732.
http://dx.doi.org/10.1097/01.ASN.0000113552.59155.72 [18] Yu, Z.H., Ding, J., Huang, J.P., Yao, Y., Xiao, H.J., Zhang, J.J., et al. (2005) Mutations in NPHS2 in Sporadic Steroid-Resistant Nephrotic Syndrome in Chinese Children. Nephrology Dialysis Transplantation, 20, 902-908. http://dx.doi.org/10.1093/ndt/gfh769 [19] Otukesh, H., Ghazanfari, B., Fereshtehnejad, S.M., Bakhshayesh, M., Hashemi, M., Hoseini, R., et al. (2009) NPHS2 Mutations in Children with Steroid-Resistant Nephritic Syndrome. Iranian Journal of Kidney Diseases, 3, 99-102. [20] Rachmadi, D., Hilmanto, D., Idjradinata, P. and Sukadi, A. (2011) NPHS2 Gene Mutation, Atopy and Gender as Risk Factors for Steroid-Resistant Nephrotic Syndrome in Indonesian. Paediatrica Indonesiana, 51, 272-276. [21] Tsukaguchi, H., Sudhakar, A., Le, T.C., Nguyen, T., Yao, J., Schwimmer, J.A., Schachter, A.D., et al. (2002) NPHS2 Mutations in Late-Onset Focal Segmental Glomerulosclerosis: R229Q Is a Common Disease-Associated Allele. Journal of Clinical Investigation, 110, 1659-1666.
http://dx.doi.org/10.1172/JCI0216242 [22] Pereira, A.C., Pereira, A.B., Mota, G.F., Cunha, R.S., Herkenhoff, F.L., Pollack, M.R., et al. (2004) NPHS2 R229Q Functional Variant Is Associated with Microalbuminuria in the General Population. Kidney International, 65, 1026-1030. http://dx.doi.org/10.1111/j.1523-1755.2004.00479.x [23] Obeidova, H., Merta, M., Reiterova, J., Maixnerova, D., Stekrova, J., Rysava, R., et al. (2006) Genetic Basis of Nephrotic Syndrome—Review. Prague Medical Report, 107, 5-16. [24] Aucella, F., De Bonis, P., Gatta, G., Muscarella, L.A., Vigilante, M., Di Giorgio, G., et al. (2004) Molecular Analysis of NPHS2 and ACTN4 Genes in a Series of 33 Italian Patients Affected by Adult-Onset Nonfamilial Focal Segmental Glomerulosclerosis. Nephron Clinical Practice, 99, 31-36.
http://dx.doi.org/10.1159/000082864 [25] Rachmadi, D., Hilmanto, D., Idjradinata, P. and Sukadi, A. (2011) NPHS2 (412 C→T and 419delG) Gene Mutation and Their Clinical Manifestation in Indonesian Steroid-Resistant Nephrotic Syndrome. Majalah Kedokteran Bandung, 43, 193-198. http://dx.doi.org/10.15395/mkb.v43n4.69