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Capturing the biology of disease severity in a PSC-based model of familial dysautonomia

Nature Medicine volume 22, pages 14211427 (2016) | Download Citation


Familial dysautonomia (FD) is a debilitating disorder that affects derivatives of the neural crest (NC). For unknown reasons, people with FD show marked differences in disease severity despite carrying an identical, homozygous point mutation in IKBKAP, encoding IκB kinase complex–associated protein. Here we present disease-related phenotypes in human pluripotent stem cells (PSCs) that capture FD severity. Cells from individuals with severe but not mild disease show impaired specification of NC derivatives, including autonomic and sensory neurons. In contrast, cells from individuals with severe and mild FD show defects in peripheral neuron survival, indicating that neurodegeneration is the main culprit for cases of mild FD. Although genetic repair of the FD-associated mutation reversed early developmental NC defects, sensory neuron specification was not restored, indicating that other factors may contribute to disease severity. Whole-exome sequencing identified candidate modifier genes for individuals with severe FD. Our study demonstrates that PSC-based modeling is sensitive in recapitulating disease severity, which presents an important step toward personalized medicine.

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We thank J.-F. Brunet (Ecole Normale Supérieure) for providing us with the PHOX2A antibody, S. Irion and M. Tomishima for critical review of the manuscript, A. Hudon for general help, H. Ralph (Weill Cornell Cell Screening Core) for image quantification and the Bioinformatics, Integrated Genomics Operations (funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology) and Flow Cytometry Core Facilities at Sloan Kettering Institute. This work was supported by the Swiss National Science Foundation (N.Z.); the US National Institutes of Health (P30CA08748), New York State Stem Cell Science (NYSTEM) (C026446 and C026447) and the Tri-institutional Stem Cell Initiative (Starr Foundation) (L.S.); and a Robertson Investigator Award from New York Stem Cell Foundation, Maryland Stem Cell Research Funding (MSCRF/TEDCO) and the Adrienne Helis Malvin Medical Research Foundation (G.L.).

Author information


  1. Developmental Biology Program, Sloan Kettering Institute, New York, New York, USA.

    • Nadja Zeltner
    • , Faranak Fattahi
    • , Nathalie Saurat
    • , Bastian Zimmer
    • , Jason Tchieu
    • , Mohamed A Soliman
    •  & Lorenz Studer
  2. Center for Stem Cell Biology, Sloan Kettering Institute, New York, New York, USA.

    • Nadja Zeltner
    • , Faranak Fattahi
    • , Nathalie Saurat
    • , Bastian Zimmer
    • , Jason Tchieu
    • , Mohamed A Soliman
    •  & Lorenz Studer
  3. Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA.

    • Faranak Fattahi
  4. Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Nicole C Dubois
  5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.

    • Fabien Lafaille
    • , Lei Shang
    •  & Jean-Laurent Casanova
  6. Weill Cornell Medical College, New York, New York, USA.

    • Mohamed A Soliman
  7. Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

    • Gabsang Lee


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N.Z.: design and conception of the study, writing of the manuscript, cell maintenance, reprogramming, GO term analysis, directed differentiation and survival assays, protocol optimization, gene targeting of PSCs and cellular and molecular assays. F.F.: AN differentiation protocol establishment and execution and survival assays in ANs. J.T.: RNA-sequencing data analysis. N.C.D.: design and execution of cardiac mesoderm differentiations. B.Z.: data quantification of scratch assay. N.S. and M.A.S.: western blotting. G.L.: reprogramming of S3 PSCs and mentoring. J.-L.C., L. Shang and F.L.: advice and analysis of whole-exome sequencing. L. Studer: design and conception of the study, data interpretation, writing of the manuscript and mentoring.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Nadja Zeltner or Lorenz Studer.

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    Supplementary Table 2

    List of candidate gene analysis from whole-exome sequencing

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