Letter | Published:

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

Nature volume 461, pages 402406 (17 September 2009) | Download Citation



The isolation of human induced pluripotent stem cells (iPSCs)1,2,3 offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs4,5,6,7. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP8 gene involved in transcriptional elongation9. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007)

  2. 2.

    et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007)

  3. 3.

    et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008)

  4. 4.

    et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 131, 1218–1221 (2008)

  5. 5.

    et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009)

  6. 6.

    et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008)

  7. 7.

    et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009)

  8. 8.

    et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605 (2001)

  9. 9.

    et al. Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol. Cell 22, 521–531 (2006)

  10. 10.

    , , & Survival in familial dysautonomia: impact of early intervention. J. Pediatr. 141, 518–523 (2002)

  11. 11.

    et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68, 753–758 (2001)

  12. 12.

    et al. Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum. Mol. Genet. 13, 429–436 (2004)

  13. 13.

    et al. Stoichiometric and temporal requirements of Oct4, Sox2, Klf4 and cMyc expression for efficient human iPSC induction and differentiation. Proc. Natl Acad. Sci. USA 106, 12759–12764 (2009)

  14. 14.

    et al. Human ES cell-derived neural rosettes reveal a functionally dinstinct early neural stem cell stage. Genes Dev. 22, 152–165 (2008)

  15. 15.

    et al. Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nature Biotechnol. 25, 1468–1475 (2007)

  16. 16.

    , , & Forced expression of HoxB4 enhances hematopoietic differentiation by human embryonic stem cells. Mol. Cells 25, 487–493 (2008)

  17. 17.

    et al. Generation of functional hemangioblasts from human embryonic stem cells. Nature Methods 4, 501–509 (2007)

  18. 18.

    et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnol. 23, 1534–1541 (2005)

  19. 19.

    , , , & Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301, 972–976 (2003)

  20. 20.

    et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature Med. 14, 125–133 (2008)

  21. 21.

    , , & The cellular function of MASH1 in autonomic neurogenesis. Neuron 15, 1245–1258 (1995)

  22. 22.

    et al. IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. J. Cell Sci. 121, 854–864 (2008)

  23. 23.

    , & EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Biochem. Biophys. Res. Commun. 310, 627–633 (2003)

  24. 24.

    , & Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem. Biophys. Res. Commun. 306, 303–309 (2003)

  25. 25.

    Familial dysautonomia: a review of the current pharmacological treatments. Expert Opin. Pharmacother. 6, 561–567 (2005)

  26. 26.

    et al. From the Cover: derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl Acad. Sci. USA 101, 12543–12548 (2004)

  27. 27.

    et al. BAC transgenesis in human ES cells as a novel tool to define the human neural lineage. Stem Cells 27, 521–532 (2009)

  28. 28.

    et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnol. 27, 275–280 (2009)

  29. 29.

    , , , & Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 109, 2679–2687 (2007)

  30. 30.

    , & Wound-healing assay. Methods Mol. Biol. 294, 23–29 (2005)

Download references


We thank J. Hendrikx, M. Leversha and C. Zhao for technical help. The work was supported by grants from the Starr Foundation and NYSTEM, by the New York Stem Cell Foundation (NYCSF, Druckenmiller fellowships to G.L. and C.A.F.) and by the Starr Scholar fellowship to S.M.C.

Author Contributions G.L.: conception and study design, maintenance and directed differentiation of iPSCs, cellular/molecular assays for disease modelling, data assembly, analysis and interpretation, and writing of manuscript; E.P.P., H.K. and C.A.F.: iPSC clone derivation and maintenance; S.M.C., M.J.T. and A.V.: data collection, analysis and interpretation; Y.M.G., J.M. and F.S.: in vivo experiments and histological analyses; V.T. and M.S.: study design, data analysis and interpretation; L.S.: conception and study design, data analysis and interpretation, and writing of manuscript.

Author information


  1. Developmental Biology Program,

    • Gabsang Lee
    • , Hyesoo Kim
    • , Stuart M. Chambers
    • , Mark J. Tomishima
    • , Christopher A. Fasano
    • , Yosif M. Ganat
    •  & Lorenz Studer
  2. Center for Cell Engineering,

    • Eirini P. Papapetrou
    • , Mark J. Tomishima
    • , Viviane Tabar
    • , Michel Sadelain
    •  & Lorenz Studer
  3. SKI Stem Cell Research Facility,

    • Mark J. Tomishima
  4. Department of Neurosurgery,

    • Jayanthi Menon
    • , Fumiko Shimizu
    • , Viviane Tabar
    •  & Lorenz Studer
  5. Genomics Core Facility, Sloan-Kettering Institute, 1275 York Ave,

    • Agnes Viale
  6. Weill Cornell Graduate School, New York, New York 10065, USA

    • Yosif M. Ganat


  1. Search for Gabsang Lee in:

  2. Search for Eirini P. Papapetrou in:

  3. Search for Hyesoo Kim in:

  4. Search for Stuart M. Chambers in:

  5. Search for Mark J. Tomishima in:

  6. Search for Christopher A. Fasano in:

  7. Search for Yosif M. Ganat in:

  8. Search for Jayanthi Menon in:

  9. Search for Fumiko Shimizu in:

  10. Search for Agnes Viale in:

  11. Search for Viviane Tabar in:

  12. Search for Michel Sadelain in:

  13. Search for Lorenz Studer in:

Corresponding author

Correspondence to Lorenz Studer.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-11 with Legends and Supplementary Tables 1-3.


  1. 1.

    Supplementary Movie 1

    This movie, shows in real-time beating putative cardiomyocytes derived from FD human iPS cell line (clone#22).

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.