Recent advances in the research on mechanisms underlying podocyte-specific gene mutation-related steroid-resistant nephrotic syndrome
ZHANG Li-Wen, WANG Le-Ping
Department of Pediatrics, Changzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu 213003, China
Abstract：Steroid-resistant nephrotic syndrome poses a significant clinical challenge. Its pathogenesis has not been fully elucidated. In recent years, numerous studies have shown that podocyte-specific gene mutations may play important roles in the development of steroid-resistant nephrotic syndrome. Among the identified genes mutated in podocytes include NPHS2, NPHS1, WT1, TRPC6, MDR1, PLCE1, LMX1B, and LAMB2. This review aims to summarize the characteristics of these mutated genes in podocytes. The putative role for these podocyte-specific mutated genes in the pathogenesis, diagnosis, treatment and prognosis of steroid-resistant nephrotic syndrome is also discussed.
McCarthy HJ, Bierzynska A, Wherlock M, et al. Simultaneous sequencing of 24 genes associated with steroid-resistant nephritic syndrome[J]. Clin J Am Soc Nephrol, 2013, 8(4): 637-648.
[2]
Ren HQ, Chen GF, Zhou X, et al. The clinical efficacy of low-dose tacrolimus combined with tripterygium to treat the steroid-resistant nephrotic syndrome[J]. Open J Nephrol, 2012, 6(2): 97-104.
[3]
Jaffer AT, Ahmed WU, Raju DS, et al. Foothold of NPHS2 mutations in primary nephrotic syndrome[J]. J Postgrad Med, 2011, 57(4): 314-320.
[4]
Otukesh H, Ghazanfari B, Fereshtehnejad SM, et al. NPHS2 mutations in children with steroid-resistant nephrotic syndrome[J]. Iran J Kidney Dis, 2009, 3(2): 99-102.
[5]
Huber TB, Schermer B, Benzing T. Podocin organizes ion channel-lipid supercomplexes: implications for mechanosensation at the slit diaphragm[J]. Nephron Exp Nephrol, 2007, 106(2): 27-31.
[6]
Kerti A, Csohany R, Szabo A, et al. NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2013, 28(5): 751-757.
[7]
Santin S, Tazon-Vega B, Silva I, et al. Clinical value of NPHS2 analysis in early-and adult-onset steroid-resistant nephrotic syndrome[J]. Clin J Am Soc Nephrol, 2011, 6(2): 344-354.
[8]
Caridi G, Bertelli R, Carrea A, et al. Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis[J]. J Am Soc Nephrol, 2001, 12(12): 2742-2746.
[9]
Troyanov S, Wall CA, Miller JA, et al. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission[J]. J Am Soc Nephrol, 2005, 16(2): 1061-1068.
[10]
Santin S, Tazon-Vega B, Silva I, et al. Clinical value of NPHS2 analysis in early and adult-onset steroid-resistant nephrotic syndrome[J]. Clin J Am Soc Nephrol, 2011, 6(2): 344-354.
Santin S, Bullich G, Tazon-Vega B, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome[J]. Clin J Am Soc Nephrol, 2011, 6(5): 1139-1148.
[15]
Yu ZH, Wang DJ, Meng DC, et al. Mutations in NPHS1 in a Chinese child with congenital nephrotic syndrome[J]. Genet Mol Res, 2012, 11(2): 1460-1464.
[16]
Machuca E, Benoit G, Nevo F, et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome[J]. J Am Soc Nephrol, 2010, 21(7): 1209-1217.
[17]
Abid A, Khaliq S, Shahid S, et al. A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan[J]. Gene, 2012, 502(2): 133-137.
[18]
Abid A, Khaliq S, Shahid S, et al. The effects of the WT1 gene on apoptosis and development-related gene expression in porcine kidney fibroblasts and swine testis cells[J]. Mol Reprod Dev, 2013, 80(5): 414-425.
[19]
Cho HY, Lee JH, Choi HJ, et al. WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2008, 23(1): 63-70.
[20]
Li J, Ding J, Zhao D, et al. WT1 gene mutations in Chinese children with early onset nephrotic syndrome[J]. Pediatr Res, 2010, 68(2): 155-158.
[21]
Chernin G, Heeringa SF, Gbadegesin R, et al. Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2008, 23(9): 1455-1460.
[22]
Megremis S, Mitsioni A, Fylaktou I, et al. Broad and unexpected phenotypic expression in Greek children with steroid-resistant nephrotic syndrome due to mutations in the Wilms' tumor 1 (WT1) gene[J]. Eur J Pediatr, 2011, 170(12): 1529-1534.
[23]
Anochie IC, Eke FU, Okpere AN. Familial focal segmental glomerulosclerosis (FSGS) in a nigerian family and exclusion of mutations in NPHS2, WT1 and APOL1[J]. West Afr J Med, 2012, 31(4): 273-276.
[24]
Xu P, Xu J, Li Z, et al. Expression of TRPC6 in renal cortex and hippocampus of mouse during postnatal development[J]. PLoS One, 2012, 7(6): e38503.
[25]
D'Esposito M, Strazzullo M, Cuccurese M, et al. Identification and assignment of the human transient receptor potential channel 6 gene TRPC6 to chromosome 11q21—>q22 [J]. Cytogenet Cell Genet, 1998, 83(1-2): 46-47.
[26]
Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype[J]. Clin J Am Soc Nephrol, 2011, 6(7): 1626-1634.
[27]
Heeringa SF, Moller CC, Du J, et al. A novel TRPC6 mutation that causes childhood FSGS[J]. PLoS One, 2009, 4(11): 7771.
[28]
Hofstra JM, Lainez S, van Kuijk WH, et al. New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis[J]. Nephrol Dial Transplant, 2013, 28(1): 324-328.
[29]
Mir S, Yavascan O, Berdeli A, et al. TRPC6 gene variants in Turkish children with steroid-resistant nephrotic syndrome[J]. Nephrol Dial Transplant, 2012, 27(1): 205-209.
[30]
Jafar T, Prasad N, Agarwal V, et al. MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children[J]. Nephrol Dial Transplant, 2011, 26(12): 3968-3974.
[31]
Ueda S, Sugimoto K, Yanagida H, et al. Low-density lipoprotein adsorption therapy can restore drug sensitivity for immunosuppressants via inhibitory effects upon MDR-1 gene expression[J]. Ther Apher Dial, 2011, 15(5): 499-503.
[32]
Boyer O, Benoit G, Gribouval O, et al. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome[J]. J Med Genet, 2010, 47(7): 445-452.
[33]
Ismaili K, Pawtowski A, Boyer O, et al. Genetic forms of nephrotic syndrome: a single-center experience in Brussels[J]. Pediatr Nephrol, 2009, 24(2): 287-294.
[34]
Chen YM, Kikkawa Y, Miner JH. A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion[J]. J Am Soc Nephrol, 2011, 22(5): 849-858.
[35]
Mbarek IB, Abroug S, Omezzine A, et al. Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children[J]. Pediatr Nephrol, 2011, 26(2): 241-249.
[36]
Rohr C, Prestel J, Heidet L, et al. The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes[J]. J Clin Invest, 2002, 109(8): 1073-1082.
[37]
Harendza S, Stahl RA, Schneider A. The transcriptional regulation of podocin (NPHS2) by Lmx1b and a promoter single nucleotide polymorphism[J]. Cell Mol Biol Lett, 2009, 14(4): 679-691.
[38]
Dai S, Wang Z, Pan X, et al. ACTN4 gene mutations and single nucleotide polymorphisms in idiopathic focal segmental glomerulosclerosis[J]. Nephron Clin Pract, 2009, 111(2): c87-c94.
[39]
Gigante M, Pontrelli P, Montemurno E, et al. CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) [J]. Nephrol Dial Transplant, 2009, 24(6): 1858-1864.
[40]
Tossidou I, Niedenthal R, Klaus M, et al. CD2AP regulates SUMOylation of CIN85 in podocytes[J]. Mol Cell Biol, 2012, 32(6): 1068-1079.
[41]
Benoit G, Machuca E, Nevo F, et al. Analysis of recessive CD2AP and ACTN4 mutations in steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2010, 25(3): 445-451.
[42]
Barua M, Brown EJ, Charoonratana VT, et al. Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis[J]. Kidney Int, 2013, 83(2): 316-322.
[43]
Lee HK, Han KH, Jung YH, et al. Variable renal phenotype in a family with an INF2 mutation[J]. Pediatr Nephrol, 2011, 26(1): 73-76.
