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Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs

Author

Listed:
  • Gabsang Lee

    (Developmental Biology Program,)

  • Eirini P. Papapetrou

    (Center for Cell Engineering,)

  • Hyesoo Kim

    (Developmental Biology Program,)

  • Stuart M. Chambers

    (Developmental Biology Program,)

  • Mark J. Tomishima

    (Developmental Biology Program,
    Center for Cell Engineering,
    SKI Stem Cell Research Facility,)

  • Christopher A. Fasano

    (Developmental Biology Program,)

  • Yosif M. Ganat

    (Developmental Biology Program,
    Weill Cornell Graduate School, New York, New York 10065, USA)

  • Jayanthi Menon

    (Department of Neurosurgery,)

  • Fumiko Shimizu

    (Department of Neurosurgery,)

  • Agnes Viale

    (Genomics Core Facility, Sloan-Kettering Institute, 1275 York Ave,)

  • Viviane Tabar

    (Center for Cell Engineering,
    Department of Neurosurgery,)

  • Michel Sadelain

    (Center for Cell Engineering,)

  • Lorenz Studer

    (Developmental Biology Program,
    Center for Cell Engineering,
    Department of Neurosurgery,)

Abstract

Familial dysautonomia: iPS cell disease model Familial dysautonomia is a rare and fatal peripheral neuropathy caused by a mutation in the gene IKBKAP that encodes a protein involved in transcriptional elongation. Lee et al. report the derivation of patient-specific iPS (induced pluripotent stem) cells and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis revealed tissue-specific mis-splicing of IKBKAP in vitro, with the patients' neural crest precursors expressing particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. Transcriptome analysis and cell-based assays showed defects in neurogenic differentiation and migration behaviour. This work is a step towards using iPS technology to produce relevant human disease models, and in functional assays for the identification of candidate drugs.

Suggested Citation

  • Gabsang Lee & Eirini P. Papapetrou & Hyesoo Kim & Stuart M. Chambers & Mark J. Tomishima & Christopher A. Fasano & Yosif M. Ganat & Jayanthi Menon & Fumiko Shimizu & Agnes Viale & Viviane Tabar & Mich, 2009. "Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs," Nature, Nature, vol. 461(7262), pages 402-406, September.
    • Handle: RePEc:nat:nature:v:461:y:2009:i:7262:d:10.1038_nature08320
    DOI: 10.1038/nature08320
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    Cited by:

    1. Ju-Chan Park & Yun-Jeong Kim & Gue-Ho Hwang & Chan Young Kang & Sangsu Bae & Hyuk-Jin Cha, 2024. "Enhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Hsueh-Fu Wu & Wenxin Yu & Kenyi Saito-Diaz & Chia-Wei Huang & Joseph Carey & Frances Lefcort & Gerald W. Hart & Hong-Xiang Liu & Nadja Zeltner, 2022. "Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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