Skip to main content
SpringerLink
Log in

Novel Pathogenic Mutation of P209L in TRPC6 Gene Causes Adult Focal Segmental Glomerulosclerosis

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 μmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Not applicable.

References

  • Ashbrook DG et al (2021) A platform for experimental precision medicine: the extended BXD mouse family. Cell Syst 12(3):235–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bahcall OG (2015) Genetic testing ACMG guides on the interpretation of sequence variants. Nat Rev Genet 16(5):256

    Article  CAS  PubMed  Google Scholar 

  • Buscher AK et al (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5(11):2075–2084

    Article  PubMed  PubMed Central  Google Scholar 

  • Buscher AK et al (2012) Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin Nephrol 78(1):47–53

    Article  MathSciNet  PubMed  Google Scholar 

  • Caster DJ et al (2022) Efficacy and safety of immunosuppressive therapy in primary focal segmental glomerulosclerosis: a systematic review and meta-analysis. Kidney Med 4(8):100501

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen YM, Liapis H (2015) Focal segmental glomerulosclerosis: molecular genetics and targeted therapies. BMC Nephrol 16:1–10

    Article  Google Scholar 

  • Dryer SE, Reiser J (2010) TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol 299(4):F689–F701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Filler G et al (2003) Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis 42(6):1107–1113

    Article  PubMed  Google Scholar 

  • Gallon L et al (2012) Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med 366(17):1648–1649

    Article  CAS  PubMed  Google Scholar 

  • Gigante M et al (2011) TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol 6(7):1626–1634

    Article  CAS  PubMed  Google Scholar 

  • Glassock RJ (1996) Primary glomerular diseases. The kidney

  • Hanafusa H et al (2021) Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis. Am J Med Genet A 185(7):2175–2179

    Article  CAS  PubMed  Google Scholar 

  • He X et al (2023) Artificial intelligence-based multi-omics analysis fuels cancer precision medicine. Semin Cancer Biol 88:187–200

    Article  CAS  PubMed  Google Scholar 

  • Heeringa SF et al (2009) A novel TRPC6 mutation that causes childhood FSGS. PLoS ONE 4(11):e7771

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Hofstra JM et al (2013) New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis. Nephrol Dial Transplant 28(7):1830–1838

    Article  CAS  PubMed  Google Scholar 

  • Junli H et al (2018) 5-HT promotes pulmonary arterial smooth muscle cell proliferation through the TRPC channel. Cell Mol Biol 64(13):89–96

    Article  PubMed  Google Scholar 

  • Kaliounji A et al (2021) A life-changing diagnosis of focal segmental glomerulosclerosis in a young hispanic male. Cureus 13(12):e20323

    PubMed  PubMed Central  Google Scholar 

  • Karimi Yazdi A et al (2018) The first successful application of preimplantation genetic diagnosis for hearing loss in Iran. Cell Mol Biol 64(9):1718

    Article  PubMed  Google Scholar 

  • Köhler S et al (2017) The human phenotype ontology in 2017. Nucleic Acids Res 45(D1):D865–D876

    Article  PubMed  Google Scholar 

  • Lee H et al (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312(18):1880–1887

    Article  PubMed  PubMed Central  Google Scholar 

  • Lepori N et al (2018) Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults. Clin Kidney J 11(2):179–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao Y et al (2019) WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res 47(W1):W199–W205

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu BC et al (2013) High glucose induces podocyte apoptosis by stimulating TRPC6 via elevation of reactive oxygen species. BBA-Mol Cell Res 1833(6):1434–1442

    CAS  ADS  Google Scholar 

  • Llavero F et al (2019) McArdle disease: new insights into its underlying molecular mechanisms. Int J Mol Sci 20(23):5919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKenna A et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meliambro K et al (2017) The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics. J Biol Chem 292(51):21137–21148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mir S et al (2012) TRPC6 gene variants in Turkish children with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 27(1):205–209

    Article  CAS  PubMed  Google Scholar 

  • Mukerji N, Damodaran TV, Winn MP (2007) TRPC6 and FSGS: the latest TRP channelopathy. Biochem Biophys Acta 1772(8):859–868

    CAS  PubMed  Google Scholar 

  • Mulligan MK et al (2017) GeneNetwork: a toolbox for systems genetics. Syst Genet 75–120

  • Nogales-Gadea G et al (2012) Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. Brain 135(7):2048–2057

    Article  PubMed  Google Scholar 

  • Nogales-Gadea G et al (2015) McArdle disease: update of reported mutations and polymorphisms in the PYGM gene. Hum Mutat 36(7):669–678

    Article  CAS  PubMed  Google Scholar 

  • Paster SB, Adams DF, Hollenberg NK (1975) Acute renal failure in McArdle’s disease and myoglobinuric states. Radiology 114(3):567–570

    Article  CAS  PubMed  Google Scholar 

  • Pavenstadt H, Kriz W, Kretzler M (2003) Cell biology of the glomerular podocyte. Physiol Rev 83(1):253–307

    Article  CAS  PubMed  Google Scholar 

  • Pfeffer CM, Ho BN, Singh ATK (2017) The evolution, functions and applications of the breast cancer genes BRCA1 and BRCA2. Cancer Genomics Proteomics 14(5):293–298

    CAS  PubMed  PubMed Central  Google Scholar 

  • Riehle M et al (2016) TRPC6 G757D loss-of-function mutation associates with FSGS. J Am Soc Nephrol 27(9):2771–2783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenberg AZ, Kopp JB (2017) Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 12(3):502–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santin S et al (2009) TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis. Nephrol Dial Transplant 24(10):3089–3096

    Article  CAS  PubMed  Google Scholar 

  • Schlöndorff J et al (2009) TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol 296(3):C558–C569

    Article  PubMed  PubMed Central  Google Scholar 

  • Shabaka A, Ribera AT, Fernández-Juárez G (2020) Focal segmental glomerulosclerosis: state-of-the-art and clinical perspective. Nephron 144(9):413–427

    Article  CAS  PubMed  Google Scholar 

  • Shkreli M et al (2012) Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nat Med 18(1):111–119

    Article  CAS  Google Scholar 

  • Sunohara M et al (2019) Upregulation of tumor susceptibility gene 101 (TSG101) by mechanical stress in podocytes. Cell Mol Biol 65(1):84–88

    Article  PubMed  Google Scholar 

  • Uffelmann E et al (2021) Genome-wide association studies. Nat Rev Methods Primers 1(1):59

    Article  CAS  Google Scholar 

  • Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164–e164

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang B et al (2023) Identification of key biomarkers in hepatocellular carcinoma induced by non-alcoholic steatohepatitis or metabolic syndrome via integrated bioinformatics analysis: biomarkers in NASH-induced hepatocellular carcinoma. Cell Mol Biol 69(7):174–180

    Article  PubMed  Google Scholar 

  • Wiggins RC (2007) The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 71(12):1205–1214

    Article  CAS  PubMed  Google Scholar 

  • Winn MP et al (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308(5729):1801–1804

    Article  CAS  PubMed  ADS  Google Scholar 

  • Wolf G, Chen SD, Ziyadeh FN (2005) From the periphery of the glomerular capillary wall toward the center of disease—podocyte injury comes of age in diabetic nephropathy. Diabetes 54(6):1626–1634

    Article  CAS  PubMed  Google Scholar 

  • Woroniecka KI et al (2011) Transcriptome analysis of human diabetic kidney disease. Diabetes 60(9):2354–2369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao S-Y et al (2019) Identification of a novel missense eya4 mutation causing autosomal dominant non"‘syndromic hearing loss in a chinese family. Cell Mol Biol 65(3):84–88

    Article  PubMed  Google Scholar 

  • Xie JY, Chen N (2013) Primary glomerulonephritis in mainland China: an overview. In: Chen N (ed) New insights into glomerulonephritis: pathogenesis and treatment, pp 1–11

  • Yang X et al (2015) miR-135 family members mediate podocyte injury through the activation of Wnt/beta-catenin signaling. Int J Mol Med 36(3):669–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu B et al (2009) Identification and functional analysis of a novel TRPC6 mutation associated with late onset familial focal segmental glomerulosclerosis in Chinese patients. Mutat Res-Fundam Mol Mech Mutagenesis 664(1–2):84–90

    Article  CAS  Google Scholar 

  • Zhuang Q et al (2021) Nuclear exclusion of YAP exacerbates podocyte apoptosis and disease progression in Adriamycin-induced focal segmental glomerulosclerosis. Lab Invest 101(2):258–270

    Article  CAS  PubMed  Google Scholar 

  • Zúñiga-García V et al (2015) Differential expression of ion channels and transporters during hepatocellular carcinoma development. Dig Dis Sci 60:2373–2383

    Article  PubMed  Google Scholar 

Download references

Funding

This research was funded by the Binzhou Medical University Research Start-up Fund (50012304486) to FX and the Taishan Scholar Program (No. Tsqn202103198) to CL.

Author information

Author notes

  1. Tianxi Yu and Yongqiang Ji have contributed equally.

Authors and Affiliations

  1. School of Clinical Medicine, Weifang Medical University, Weifang, 261042, China

    Tianxi Yu, Xin Cui & Ning Liang

  2. Department of Nephrology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China

    Yongqiang Ji & Yan Zhang

  3. Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China

    Tianxi Yu, Xin Cui, Ning Liang, Shuang Wu, Chongjun Xiang, Yue Li, Huiying Tao, Yaqi Xie, Hongwei Zuo & Chunhua Lin

  4. The 2nd Medical College of Binzhou Medical University, Yantai, 264003, Shandong, China

    Chongjun Xiang, Yue Li, Huiying Tao, Yaqi Xie & Hongwei Zuo

  5. Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China

    Wenting Wang

  6. Department of Biology, Faculty of Biological and Biomedical Sciences, The University of Haripur, Haripur, KP, Pakistan

    Nauman Khan & Kamran Ullah

  7. Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, Shandong, China

    Fuyi Xu

Authors
  1. Tianxi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongqiang Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ning Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chongjun Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huiying Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yaqi Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hongwei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wenting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nauman Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kamran Ullah
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fuyi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Chunhua Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Data analysis: YJ, XC, NL, and SW; Funding acquisition: FX and CL; Methodology: TY, FX, and WW; Supervision: CL and YZ; Visualization: CX, YL, and HT; Information collection: YX and HZ; Writing—original draft: TY and YJ; Writing—review & editing: FX, YZ, NK, and KU.

Corresponding authors

Correspondence to Yan Zhang or Chunhua Lin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical Approval

Yantai Yuhuangding Hospital Ethics Committee approved the study protocol.

Consent to Participate

Patient consent was obtained.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, T., Ji, Y., Cui, X. et al. Novel Pathogenic Mutation of P209L in TRPC6 Gene Causes Adult Focal Segmental Glomerulosclerosis. Biochem Genet (2024). https://doi.org/10.1007/s10528-023-10651-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10528-023-10651-y

Keywords

Search

Navigation