Skip to main content
SpringerLink
Log in

Establishment and characterization of ZJUCHi003: an induced pluripotent stem cell line from a patient with Temple–Baraitser/Zimmermann–Laband syndrome carrying KCNH1 c.1070G > A (p.R357Q) variant

  • Cell Line
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Pathogenic variants of the KCNH1 gene can cause dominant-inherited Temple–Baraitser/Zimmermann–Laband syndrome with severe mental retardation, seizure, gingival hyperplasia and nail hypoplasia. This study established an induced pluripotent stem cell (iPSC) line using urinary cells from a girl with KCNH1 recurrent/hotspot pathogenic variant c.1070G > A (p.R357Q). The cell identity, pluripotency, karyotypic integrity, absence of reprogramming virus and mycoplasma contamination, and differential potential to three germ layers of the iPSC line, named as ZJUCHi003, were characterized and confirmed. Furthermore, ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons. This cell line will be useful for investigating the pathogenic mechanisms of KCNH1 variants-associated symptoms, as well as for evaluating novel therapeutic approaches.

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

Similar content being viewed by others

References

  1. Mastrangelo M, Scheffer IE, Bramswig NC, et al. Epilepsy in KCNH1-related syndromes. Epileptic Disord. 2016;18(2):123–36.

    Article  PubMed  Google Scholar 

  2. Simons C, Rash L, Crawford J, et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet. 2015;47(1):73–7.

    Article  CAS  PubMed  Google Scholar 

  3. Tian M, Li R, Yang F, et al. Phenotypic expansion of KCNH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub-regional locations. CNS Neurosci Ther. 2023;29:270–81.

    Article  CAS  PubMed  Google Scholar 

  4. Tidball A, Parent J. Concise review: exciting cells: modeling genetic epilepsies with patient-derived induced pluripotent stem cells. Stem Cells. 2016;34(1):27–33.

    Article  PubMed  Google Scholar 

  5. Palasantzas V, Tamargo-Rubio I, Le K, et al. iPSC-derived organ-on-a-chip models for personalized human genetics and pharmacogenomics studies. Trends Genet. 2023;39(4):268–84.

    Article  CAS  PubMed  Google Scholar 

  6. Silva-Pedrosa R, Salgado A, Ferreira P. Revolutionizing disease modeling: the emergence of organoids in cellular systems. Cells. 2023;12(6):930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Javaid M, Tan T, Dvir N, et al. Human in vitro models of epilepsy using embryonic and induced pluripotent stem cell. Cells. 2022;11(24):3957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hirose S, Tanaka Y, Shibata M, et al. Application of induced pluripotent stem cells in epilepsy. Mol Cell Neurosci. 2020;108: 103535.

    Article  CAS  PubMed  Google Scholar 

  9. Gripp KW, Smithson SF, Scurr IJ, et al. Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K(+) channelopathies. Eur J Hum Genet. 2021;29(9):1384–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bertoli-Avella A, Beetz C, Ameziane N, et al. Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. Eur J Hum Genet. 2021;29(1):141–53.

    Article  CAS  PubMed  Google Scholar 

  11. Geisheker M, Heymann G, Wang T, et al. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci. 2017;20(8):1043–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fukai R, Saitsu H, Tsurusaki Y, et al. De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures. J Hum Genet. 2016;61(5):381–7.

    Article  CAS  PubMed  Google Scholar 

  13. Bramswig NC, Ockeloen CW, Czeschik JC, et al. ‘Splitting versus lumping’: temple-Baraitser and Zimmermann-Laband syndromes. Hum Genet. 2015;134(10):1089–97.

    Article  CAS  PubMed  Google Scholar 

  14. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinform. 2013;43(11):1–11.

    Google Scholar 

  15. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26:2867–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38: e164.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Neaverson A, Andersson M, Arshad O, et al. Differentiation of human induced pluripotent stem cells into cortical neural stem cells. Front Cell Dev Biol. 2023;10:1023340.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhou T, Benda C, Dunzinger S, et al. Generation of human induced pluripotent stem cells from urine samples. Nat Protoc. 2012;7(12):2080–9.

    Article  CAS  PubMed  Google Scholar 

  21. Martin S, Oliveira C, Queiroz F, et al. Eag1 potassium channel immunohistochemistry in the CNS of adult rat and selected regions of human brain. Neuroscience. 2008;155(3):833–44.

    Article  CAS  PubMed  Google Scholar 

  22. Cázares-Ordoñez V, Pardo L. Kv10.1 potassium channel: from the brain to the tumors. Biochem Cell Biol. 2017;95(5):531–6.

    Article  PubMed  Google Scholar 

  23. Bauer C, Schwarz J. Physiology of EAG K+Channels. J Membr Biol. 2001;182:1–15.

    Article  CAS  PubMed  Google Scholar 

  24. Kortüm F, Caputo V, Bauer C, et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann–Laband syndrome. Nat Genet. 2015;47(6):661–7.

    Article  PubMed  Google Scholar 

  25. Sánchez A, Urrego D, Pardo L. Cyclic expression of the voltage-gated potassium channel KV10.1 promotes disassembly of the primary cilium. EMBO Rep. 2016;17(5):708–23.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jiao J, Yang Y, Shi Y, et al. Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons. Hum Mol Genet. 2013;22:4241–52.

    Article  CAS  PubMed  Google Scholar 

  27. Liu J, Gao C, Chen W, et al. CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation. Transl Psychiatry. 2016;6: e703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim H, Quan Z, Kim Y, et al. Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients. Brain Dev. 2018;40:287–98.

    Article  PubMed  Google Scholar 

  29. Niu W, Siciliano B, Wen Z. Modeling tuberous sclerosis complex with human induced pluripotent stem cells. World J Pediatr. 2022; Online ahead of print. PMID: 35759110. https://link.springer.com/article/10.1007/s12519-022-00576-8

  30. Papazian DM, Timpe LC, Jan YN, Jan LY. Alteration of voltage-dependence of Shaker potassium channel by mutations in the S4 sequence. Nature. 1991;349:305–10.

    Article  CAS  PubMed  Google Scholar 

  31. Catterall WA. Ion channel voltage sensors: structure, function, and pathophysiology. Neuro. 2010;67(6):915–28.

    CAS  Google Scholar 

Download references

Funding

This study was supported by the Fundamental Research Funds for the Central Universities of China (226–2022-00035).

Author information

Author notes

  1. Die Chen, Jimei Su and Xueying Huang are contributed equally.

Authors and Affiliations

  1. Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Die Chen, Hongyu Chen, Chunchun Zhi, Zuolin Zhou, Lan Yu & Xiaoling Jiang

  2. Key Laboratory of Genetic and Developmental Disorders of Zhejiang Province, Hangzhou, China

    Die Chen, Chunchun Zhi, Zuolin Zhou & Xiaoling Jiang

  3. Department of Stomatology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Jimei Su

  4. Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Tongji University, Shanghai, 201204, China

    Xueying Huang & Bing Zhang

  5. Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Tiejia Jiang

Authors
  1. Die Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jimei Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tiejia Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chunchun Zhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zuolin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoling Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lan Yu or Xiaoling Jiang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Chen, D., Su, J., Huang, X. et al. Establishment and characterization of ZJUCHi003: an induced pluripotent stem cell line from a patient with Temple–Baraitser/Zimmermann–Laband syndrome carrying KCNH1 c.1070G > A (p.R357Q) variant. Human Cell 37, 832–839 (2024). https://doi.org/10.1007/s13577-024-01031-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-024-01031-8

Keywords

Search

Navigation