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01-07-2017 | Original Article

Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome

Authors: Fang Wang, Yanqin Zhang, Jianhua Mao, Zihua Yu, Zhuwen Yi, Li Yu, Jun Sun, Xiuxiu Wei, Fangrui Ding, Hongwen Zhang, Huijie Xiao, Yong Yao, Weizhen Tan, Svjetlana Lovric, Jie Ding, Friedhelm Hildebrandt

Published in: Pediatric Nephrology | Issue 7/2017

Abstract

Background

The aim of this study was to elucidate whether genetic screening test results of pediatric patients with steroid-resistant nephrotic syndrome (SRNS) vary with ethnicity.

Methods

Using high-throughput DNA sequencing, 28 nephrotic syndrome-related genes were analyzed in 110 chil-dren affected by SRNS and 10 children with isolated proteinuria enrolled by 5 centers in China (67 boys, 53 girls). Their age at disease onset ranged from 1 day to 208 months (median, 48.8 months). Patients were excluded if their age at onset of disease was over 18 years or if they were diagnosed as having Alport syndrome.

Results

A genetic etiology was identified in 28.3% of our cohort and the likelihood of establishing a genetic diagnosis decreased as the age at onset of nephrotic syndrome increased. The most common mutated genes were ADCK4 (6.67%), NPHS1 (5.83%), WT1 (5.83%), and NPHS2 (3.33%), and the difference in the frequencies of ADCK4 and NPHS2 mutations between this study and a study on monogenic causes of SRNS in the largest international cohort of 1,783 different families was significant. A case of congenital nephrotic syndrome was attributed to a homozygous missense mutation in ADCK4, and a de novo missense mutation in TRPC6 was detected in a case of infantile nephrotic syndrome.

Conclusions

Our results showed that, in the first and the largest multicenter cohort of Chinese pediatric SRNS reported to date, ADCK4 is the most common causative gene, whereas there is a low prevalence of NPHS2 mutations. Our data indicated that the genetic testing results for pediatric SRNS patients vary with different ethnicities, and this information will help to improve management of the disease in clinical practice.

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Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1997) Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International study of kidney disease in children. J Am Soc Nephrol 8:769–776PubMed

Tune BM, Mendoza SA (1997) Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J Am Soc Nephrol 8:824–832PubMed

Arbus GS, Poucell S, Bacheyie GS, Baumal R (1982) Focal segmental glomerulosclerosis with idiopathic nephrotic syndrome: three types of clinical response. J Pediatr 101:40–45CrossRefPubMed

Kin JS, Bellew CA, Silverstein DM, Aviles DH, Boineau FG, Vehaskari VM (2005) High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int 68:1275–1281CrossRef

Mekahli D, Liutkus A, Ranchin B, Yu A, Bessenay L, Girardin E, Van Damme-Lombaerts R, Palcoux JB, Cachat F, Lavocat MP, Bourdat-Michel G, Nobili F, Cochat P (2009) Long-term outcome of idiopathic steroid resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol 24:525–532CrossRef

Buscher AK, Kranz B, Buscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Broking E, Wingen AM, John U, Markus K, Monnens L, Hoyer PF, Weber S, Konrad M (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:2075–2084CrossRefPubMedPubMedCentral

Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L, Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E, Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M, Romagnani P (2015) Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol 26:230–236CrossRefPubMed

Joshi S, Andersen R, Jespersen B, Rittig S (2013) Genetics of steroid-resistant nephrotic syndrome: a review of mutation spectrum and suggested approach for genetic testing. Acta Paediatr 102:844–856CrossRefPubMed

Brown EJ, Pollak MR, Barua M (2014) Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int 85:1030–1038CrossRefPubMedPubMedCentral

10.

Piscione TD, Licht C (2011) Genetics of proteinuria: an overview of gene mutations associated with nonsyndromic proteinuric glomerulopathies. Adv Chronic Kidney Dis 18:273–289CrossRefPubMed

11.

Bierzynska A, Soderquest K, Koziell A (2015) Genes and podocytes-new insights into mechanisms of podocytopathy. Front Endocrinol (Lausanne) 5:226

12.

Santín S, Bullich G, Tazon-Vega B, García-Maset R, Gimenez I, Silva I, Ruíz P, Ballarín 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 6:1139–1148CrossRefPubMedPubMedCentral

13.

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 25:1621–1632CrossRefPubMedPubMedCentral

14.

McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJA, Christian M, Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA (2013) Simultaneous sequencing of 24 genes associated with steroid-Resistant nephrotic syndrome. Clin J Am Soc Nephrol 8:637–648CrossRefPubMedPubMedCentral

15.

Lovric S, Fang H, Vega-Warner V, Sadowski CE, Gee HY, Halbritter J, Shazia A, Saisawat P, Soliman NA, Kari JA, Otto EA, Hildebrandt F (2014) Rapid detection of monogenic causes of childhood onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 9:1109–1116CrossRefPubMedPubMedCentral

16.

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, SRNS Study Group, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289CrossRefPubMed

17.

Bullich G, Trujillano D, Santín S, Ossowski S, Mendizábal S, Fraga G, Madrid Á, Ariceta G, Ballarín J, Torra R, Estivill X, Ars E (2015) Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity. Eur J Hum Genet 23:192–199CrossRef

18.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Heqde MR, Lyon E, Ward BE, Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 10:294–300CrossRefPubMed

19.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and Guidelines for the Interpretation of Sequence Variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentral

20.

Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S, Wada N, Takahashi Y, Kaku Y, Satomura K, Ikeda M, Honda M, Iijima K, Yoshikawa N (2005) Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney Int 67:1248–1255CrossRefPubMed

21.

Schultheiss M, Ruf RG, Mucha BE, Wiggins R, Fuchshuber A, Lichtenberger A, Hildebrandt F (2004) No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations. Pediatr Nephrol 19:1340–1348CrossRefPubMed

22.

Ulinski T, Aoun B, Toubiana J, Vitkevic R, Bensman A, Donadieu J (2009) Neutropenia in congenital nephrotic syndrome of the Finnish type: role of urinary ceruloplasmin loss. Blood 113:4820–4821CrossRefPubMed

23.

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 (1998) Positionally cloned gene for a novel glomerular protein-nephrin-is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582CrossRefPubMed

24.

Shi Y, Ding J, Liu JC, Wang H, Bu DF (2005) NPHS1 mutations in a Chinese family with congenital nephrotic syndrome. Zhonghua Er Ke Za Zhi 43:805–809PubMed

25.

Lenkkeri U, Mannikko M, McCready P, Lamerdin J, Gribouval O, Niaudet P, Antignac C, Kashtan CE, Holmberg C, Kestila M, Tryggvason K (1999) Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64:51–61CrossRefPubMedPubMedCentral

26.

Sun H, Zhou W, Wang J, Yin L, Lu Y, Fu Q (2009) A novel mutation in NPHS2 gene identified in a Chinese pedigree with autosomal recessive steroid-resistant nephrotic syndrome. Pathology 41:661–665CrossRefPubMed

27.

Caridi G, Bertelli R, Carrea A, Di Duca M, Catarsi P, Artero M, Carraro M, Zennaro C, Candiano G, Musante L, Seri M, Ginevri F, Perfumo F, Ghiggeri GM (2001) Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J Am Soc Nephrol 12:2742–2746PubMed

28.

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 24:349–354CrossRefPubMed

29.

Korkmaz E, Lipska-Zietkiewicz BS, Boyer O, Gribouval O, Fourrage C, Tabatabaei M, Schnaidt, Gucer S, Kaymaz F, Arici M, Dinckan A, Mir S, Bayazit AK, Emre S, Balat A, Rees L, Shroff R, Bergmann C, Mourani C, Antignac C, Ozaltin F, Schaefer F, the PodoNet Consortium (2016) ADCK4-associated glomerulopathy causes adolescence-onset FSGS. J Am Soc Nephrol 27:63–68CrossRefPubMed

30.

Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschké P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Böckenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179–5189CrossRefPubMedPubMedCentral

31.

Pelletier J, Bruening W, Kashtan CE, Mauer M, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silveman BL, Haber DA, Housman D (1991) Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447CrossRefPubMed

32.

Miyoshi Y, Santo Y, Tachikawa K, Namba N, Hirai H, Mushiake S, Nakajima S, Michigami T, Ozono K (2006) Lack of puberty despite elevated estradiol in a 46, XY phenotypic female with Frasier syndrome. Endocr J 53:371–376CrossRefPubMed

33.

Barbaux S, Niaudet P, Gubler MC, Grünfeld 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 17:467–470CrossRefPubMed

34.

Bruening W, Bardeesy N, Silverman BL, Cohn RA, Machin GA, Aronson AJ, Housman D, Pelletier J (1992) Germline intronic and exonic mutations in the Wilms’ tumour gene (WT1) affecting urogenital development. Nat Genet 1:144–148CrossRefPubMed

35.

Boyer O, Woerner S, Yang F, Oakeley EJ, Linghu B, Gribouval O, Tête MJ, Duca JS, Klickstein L, Damask AJ, Szustakowski JD, Heibel F, Matignon M, Baudouin V, Chantrel F, Champigneulle J, Martin L, Nitschké P, Gubler MC, Johnson KJ, Chibout SD, Antignac C (2013) LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol 24:1216–1222CrossRefPubMedPubMedCentral

36.

Cho HY, Lee JH, Choi HJ, Lee BH, Ha IS, Choi Y, Cheong HI (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:63–70CrossRefPubMed

37.

Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu JH, 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–e919CrossRefPubMed

38.

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 13:400–405PubMed

39.

Ogino D, Hashimoto T, Hattori M, Sugawara N, Akioka Y, Tamiya G, Makino S, Toyota K, Mitsui T, Hayasaka K (2016) Analysis of the genes responsible for steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis in Japanese patients by whole exome sequencing analysis. J Hum Genet 61:137–141CrossRefPubMed

40.

Yu ZH, Ding J, Huang JP, Yao Y, Xiao HJ, Zhang JJ, Liu JC, Yang JY (2005) Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children. Nephrol Dial Transplant 20:902–908CrossRefPubMed

41.

Chernin G, Heeringa SF, Gbadegesin R, Liu JH, Hinkes BG, Vlangos CN, Vega-Warner V, Hildebrandt F (2008) Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:1455–1460CrossRefPubMed

42.

Mao JH, Zhang Y, Du LZ, Dai YW, Gu WZH, Liu AM, Shang SHQ, Liang L (2007) NPHS1 and NPHS2 gene mutations in Chinese children with sporadic nephrotic syndrome. Pediatr Res 61:117–122CrossRefPubMed

43.

Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E, Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T, Ozkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Ozcakar ZB, Sallay P, Cakar N, Galanti M, Terzic J, Aoun B, Afonso AC, Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F (2015) Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600CrossRefPubMedPubMedCentral

44.

Lipska BS, Iatropoulos P, Maranta R, CaridG OF, Anarat A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B, Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, Davitaia T, Wasilewska A, Drozdz D, Szczepanska M, Jankauskiene A, Higuita LMS, Ardissino G, Ozkaya O, Kuzma-Mroczkowska E, Soylemezoglu O, Ranchin B, Medynska A, Tkaczyk M, Peco-Antic A, Akil I, Jarmolinski T, Firszt-Adamczyk A, Dusek J, Simonetti GD, Gok F, Gheissari A, Emma F, Krmar RT, Fischbach M, Printza N, Simkova E, Mele C, Ghiggeri GM, Schaefer F, the PodoNet Consortium (2013) Genetic screening in adolescents with steroidresistant nephrotic syndrome. Kidney Int 84:206–213CrossRefPubMed

Title: Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome
Authors: Fang Wang
Yanqin Zhang
Jianhua Mao
Zihua Yu
Zhuwen Yi
Li Yu
Jun Sun
Xiuxiu Wei
Fangrui Ding
Hongwen Zhang
Huijie Xiao
Yong Yao
Weizhen Tan
Svjetlana Lovric
Jie Ding
Friedhelm Hildebrandt
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 7/2017
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-017-3590-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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