TRPC6 and NPHS2 gene variants in adult patients with steroid-resistant nephrotic syndrome in North-West of Iran
- 84 Downloads
Podocyte gene mutations and their role in the development of nephrotic syndrome (NS) have been reported in some ethnic groups. The aim of this study was to evaluate the presence of possible variants in TRCP6 and NPHS2 (podocin) genes and their association with clinical manifestations in a group of adult patients with steroid resistant nephrotic syndrome (SRNS). All participants including 36 patients with SRNS and 71 healthy volunteers were genotyped using polymerase chain reaction (PCR) and direct sequencing. Whole exons of NPHS2 gene and −254 C > G, −218 C > T, and −361 A > T polymorphisms in the promoter of TRPC6 gene were studied. There were no significant differences in the allele and genotype frequencies of aforementioned TRCP6 polymorphisms between cases and controls (P > 0.05). However, four novel polymorphisms including − 257 T > C, − 266 G > A, − 293 G > C, and − 21 G > A found in the promoter region of TRPC6 gene that may be involved in SRNS in our cohort. In NPHS2 gene, three different polymorphisms in the NPHS2 gene were found in 7 patients with FSGS and none of the previously reported risk polymorphisms was detected in our patients. Podocin related mutations are not too much associated with SRNS in adults, but we should consider the possibility of TRPC6 gene mutation in this population.
KeywordsGlucocorticoids Steroid resistance Late-onset SRNS Podocyte mutations Podocin Azari population
This research was funded by National Institute for Medical Research Development (NIMAD Grant No. 958376).
Compliance with ethical standards
Conflict of interest
The authors declared no potential conflicts of interest.
Present study was certified by the Ethics Committee of National Institute for Medical Research Development (NIMAD). All the procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was taken from all participants after explaining the purpose of the study.
- 6.Gigante M, Caridi G, Montemurno E, Soccio M, d’Apolito M, Cerullo G, Aucella F, Schirinzi A, Emma F, Massella L, Messina G, De Palo T, Ranieri E, Ghiggeri GM, Gesualdo L (2011) TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol 6(7):1626–1634. https://doi.org/10.2215/cjn.07830910 CrossRefPubMedGoogle Scholar
- 9.Bouchireb K, Boyer O, Gribouval O, Nevo F, Huynh-Cong E, Moriniere V, Campait R, Ars E, Brackman D, Dantal J, Eckart P, Gigante M, Lipska BS, Liutkus A, Megarbane A, Mohsin N, Ozaltin F, Saleem MA, Schaefer F, Soulami K, Torra R, Garcelon N, Mollet G, Dahan K, Antignac C (2014) NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum. Hum Mutat 35(2):178–186. https://doi.org/10.1002/humu.22485 CrossRefPubMedGoogle Scholar
- 12.Alharthi AA, Gaber A, AbuKhatwah MW, Almalki AM, Muzallef AA, Hassan MM, El-Hallous EI, Dalbouh MM, Ali GH, Atyah HM (2017) Mutational analysis of NPHS2 and WT1 genes in Saudi children with nephrotic syndrome. Curr Pediatr Res 21(1)Google Scholar
- 13.Eknoyan G, Eckardt K, Kasiske B (2012) KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2(2):1–185Google Scholar
- 14.Del Monaco M, Covello SP, Kennedy SH, Gilinger G, Litwack G, Uitto J (1997) Identification of novel glucocorticoid-response elements in human elastin promoter and demonstration of nucleotide sequence specificity of the receptor binding. J Invest Dermatol 108(6):938–942. https://doi.org/10.1111/1523-1747.ep12295241 CrossRefPubMedGoogle Scholar
- 16.Lu BC, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, Arber S, Hassell J, MacNeil L, Hoshi M, Jain S, Asai N, Takahashi M, Schmidt-Ott KM, Barasch J, D’Agati V, Costantini F (2009) Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat Genet 41(12):1295–1302. https://doi.org/10.1038/ng.476 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Zhu B, Chen N, Wang ZH, Pan XX, Ren H, Zhang W, Wang WM (2009) Identification and functional analysis of a novel TRPC6 mutation associated with late onset familial focal segmental glomerulosclerosis in Chinese patients. Mutat Res 664(1–2):84–90. https://doi.org/10.1016/j.mrfmmm.2008.11.021 CrossRefPubMedGoogle Scholar
- 18.Kuang XY, Huang WY, Xu H, Shi Y, Zhang XL, Niu XL, Wu Y, Mei CZ, Zha XL, Zhao ZH, Zhang ZG (2013) 254C > G: a TRPC6 promoter variation associated with enhanced transcription and steroid-resistant nephrotic syndrome in Chinese children. Pediatr Res 74(5):511–516. https://doi.org/10.1038/pr.2013.144 CrossRefPubMedGoogle Scholar
- 19.Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX (2009) A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119(17):2313–2322. https://doi.org/10.1161/circulationaha.108.782458 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Obeidova L, Reiterova J, Lnenicka P, Stekrova J, Safrankova H, Kohoutova M, Tesar V (2012) TRPC6 gene variants in Czech adult patients with focal segmental glomerulosclerosis and minimal change disease. Folia Biol (Praha) 58(4):173–176Google Scholar
- 23.Chen WC, Chen SY, Chen CH, Chen HY, Lin YW, Ho TJ, Huang YC, Shen JL, Tsai FJ, Chen YH (2010) Lack of association between transient receptor potential cation channel 6 polymorphisms and primary membranous glomerulonephritis. Ren Fail 32(6):666–672. https://doi.org/10.3109/0886022x.2010.485289 CrossRefPubMedGoogle Scholar
- 25.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(7):727–735. https://doi.org/10.1038/ki.2008.650 CrossRefPubMedGoogle Scholar
- 26.Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26(6):1279–1289CrossRefGoogle Scholar
- 28.Santin S, Tazon-Vega B, Silva I, Cobo MA, Gimenez I, Ruiz P, Garcia-Maset R, Ballarin J, Torra R, Ars E (2011) Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6(2):344–354. https://doi.org/10.2215/cjn.03770410 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.He N, Zahirieh A, Mei Y, Lee B, Senthilnathan S, Wong B, Mucha B, Hildebrandt F, Cole DE, Cattran D, Pei Y (2007) Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2(1):31–37. https://doi.org/10.2215/cjn.02690806 CrossRefPubMedGoogle Scholar
- 32.Tory K, Menyhard DK, Woerner S, Nevo F, Gribouval O, Kerti A, Straner P, Arrondel C, Huynh Cong E, Tulassay T, Mollet G, Perczel A, Antignac C (2014) Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 46(3):299–304. https://doi.org/10.1038/ng.2898 CrossRefPubMedGoogle Scholar