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Nat Med. 2016 Dec;22(12):1421-1427. doi: 10.1038/nm.4220. Epub 2016 Nov 14.

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

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Developmental Biology Program, Sloan Kettering Institute, New York, New York, USA.
Center for Stem Cell Biology, Sloan Kettering Institute, New York, New York, USA.
Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.
Weill Cornell Medical College, New York, New York, USA.
Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA.


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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