Mutational spectrum and novel candidate genes in Chinese children with sporadic steroid-resistant nephrotic syndrome

Abstract

Background

Approximately 10–20% of children with idiopathic nephrotic syndrome (NS) fail to respond to steroid therapy. NS is divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). Over 45 recessive and dominant genes have been found to be associated with SRNS and/or focal segmental glomerulosclerosis (FSGS).

Methods

Targeted sequencing of 339 candidate genes, expressed in glomerular filtration barrier or located in the signaling pathway of podocyte function, were sequenced by NGS in a cohort of total 89 Chinese Han children (29 sporadic SRNS, 33 sporadic SSNS, and 27 healthy).

Results

Two variants (WT1 p.R441X and NPHS2 p.G149V) were screened out as pathogenic mutations and 14 variants were likely pathogenic. Mutations of KIRREL2 (SRNS vs SSNS: 24.1% vs 3.0%, adjusted OR = 10.11, 95% CI: 1.56–198.66, P = 0.039) were significantly associated with the risk of pediatric sporadic SRNS. Besides, three pathogenic or likely pathogenic variants were identified in HP gene.

Conclusion

Two pathogenic mutations and 14 likely pathogenic mutations were discovered through targeted sequencing of 339 candidate genes. Two genes, HP and KIRREL2, as candidate genes, were first proposed to be associated with the risk of pediatric sporadic SRNS.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Gipson, D. S. et al. Management of childhood onset nephrotic syndrome. Pediatrics 124, 747–757 (2009).

  2. 2.

    Hahn, D., Hodson, E. M., Willis, N. S. & Craig, J. C. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst. Rev. 3, CD001533 (2015).

  3. 3.

    Mekahli, D. et al. Long-term outcome of idiopathic steroid resistant nephrotic syndrome: a multicenter study. Pediatr. Nephrol. 24, 1525–1532 (2009).

  4. 4.

    Giglio, S. et al. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J. Am. Soc. Nephrol. 26, 230–236 (2015).

  5. 5.

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

  6. 6.

    Brown, E. J., Pollak, M. R. & Barua, M. Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int. 85, 1030–1038 (2014).

  7. 7.

    Lovric, S., Ashraf, S., Tan, W. & Hildebrandt, F. Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrol. Dial. Transplant. 31, 1802–1813 (2016).

  8. 8.

    Tasic, V., Gucev, Z. & Polenakovic, M. Steroid resistant nephrotic syndrome-genetic consideration. Pril. (Makedon. Akad. Nauk. Umet. Odd. Med. Nauk.) 36, 5–12 (2015).

  9. 9.

    Becherucci, F. et al. Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome? J. Nephrol. 29, 543–550 (2016).

  10. 10.

    Ha, T.-S. Genetics of hereditary nephrotic syndrome: a clinical review. Korean J. Pediatr. 60, 55–63 (2017).

  11. 11.

    Sadowski, C. E. et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1279–1289 (2015).

  12. 12.

    Maruyama, K. et al. NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. Pediatr. Nephrol. 18, 412–416 (2003).

  13. 13.

    Li, J. et al. WT1 gene mutations in Chinese children with early onset nephrotic syndrome. Pediatr. Res. 68, 155–158 (2010).

  14. 14.

    Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S. & Goldstein, D. B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709 (2013).

  15. 15.

    Little, M. H. et al. Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc. Natl. Acad. Sci. USA 89, 4791–4795 (1992).

  16. 16.

    Little, M. H. et al. Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum. Mol. Genet. 2, 259–264 (1993).

  17. 17.

    Schumacher, V. et al. Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc. Natl. Acad. Sci. USA 94, 3972–3977 (1997).

  18. 18.

    Wang, F. et al. Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr. Nephrol. 32, 1181–1192 (2017).

  19. 19.

    Wang, Y. et al. Mutation spectrum of genes associated with steroid-resistant nephrotic syndrome in Chinese children. Gene 625, 15–20 (2017).

  20. 20.

    Haugen, T. H., Hanley, J. M. & Heath, E. C. Haptoglobin: a novel mode of biosynthesis of a liver secretory glycoprotein. J. Biol. Chem. 256, 1055–1057 (1981).

  21. 21.

    Asleh, R. et al. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 92, 1193–1200 (2003).

  22. 22.

    Teye, K. et al. A-61C and C-101G Hp gene promoter polymorphisms are, respectively, associated with ahaptoglobinaemia and hypohaptoglobinaemia in Ghana. Clin. Genet. 64, 439–443 (2003).

  23. 23.

    Wen, Q. et al. Proteomic profiling identifies haptoglobin as a potential serum biomarker for steroid-resistant nephrotic syndrome. Am. J. Nephrol. 36, 105–113 (2012).

  24. 24.

    Sellin, L. et al. NEPH1 defines a novel family of podocin interacting proteins. FASEB J. 17, 115–117 (2003).

  25. 25.

    Ihalmo, P. et al. Expression of filtrin in human glomerular diseases. Nephrol. Dial. Transplant. 22, 1903–1909 (2007).

  26. 26.

    Littman, M. P., Wiley, C. A., Raducha, M. G. & Henthorn, P. S. Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft-coated Wheaten Terrier dogs. Mamm. Genome 24, 119–126 (2013).

  27. 27.

    Voskarides, K. et al. A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population. PLoS ONE 12, e0174274 (2017).

  28. 28.

    Inoue, O., Suzuki-Inoue, K., Dean, W. L., Frampton, J. & Watson, S. P. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J. Cell Biol. 160, 769–780 (2003).

  29. 29.

    Kim, S.-H., Turnbull, J. & Guimond, S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 209, 139–151 (2011).

  30. 30.

    Lane-Serff, H., Sun, Y., Metcalfe, P. & Wright, G. J. Expression of recombinant ITGA2 and CD109 for the detection of human platelet antigen (HPA)-5 and -15 alloantibodies. Br. J. Haematol. 161, 453–455 (2013).

  31. 31.

    Peterson, J. A. et al. New low-frequency platelet glycoprotein polymorphisms associated with neonatal alloimmune thrombocytopenia. Transfusion 50, 324–333 (2010).

  32. 32.

    Girgert, R. et al. Integrin α2-deficient mice provide insights into specific functions of collagen receptors in the kidney. Fibrogenesis Tissue Repair 3, 19 (2010).

  33. 33.

    Rubel, D. et al. Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice. Matrix Biol. 34, 13–21 (2014).

  34. 34.

    Arrondel, C. et al. Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J. Am. Soc. Nephrol. 13, 65–74 (2002).

  35. 35.

    Galeano, D., Zanoli, L., L’Imperio, V., Fatuzzo, P. & Granata, A. Renal diseases related to MYH9 disorders. G. Ital. Nefrol. 34, 40–57 (2017).

  36. 36.

    Cechova, S. et al. MYH9 E1841K mutation augments proteinuria and podocyte injury and migration. J. Am. Soc. Nephrol. 29, 155–167 (2018).

Download references

Acknowledgements

We are indebted to the patients and families for participating in this study and to the clinical teams involved in recruitment and sample collection. This work was supported by the National Natural Science Foundation of China (81100504, 81570649).

Author information

Correspondence to Jianguo Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark