Genome-wide Analysis of Familial Dysautonomia and Kinetin Target Genes With Patient Olfactory Ecto-Mesenchymal Stem Cells

Hum Mutat. 2012 Mar;33(3):530-40. doi: 10.1002/humu.22010. Epub 2012 Jan 17.


Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder. The most common mutation is a c.2204+6T>C transition in the 5' splice site (5'ss) of IKBKAP intron 20, which causes a tissue-specific skipping of exon 20, resulting in lower synthesis of IKAP/hELP1 protein. To better understand the specificity of neuron loss in FD, we modeled the molecular mechanisms of IKBKAP mRNA splicing by studying human olfactory ecto-mesenchymal stem cells (hOE-MSCs) derived from FD patient nasal biopsies. We explored how the modulation of IKBKAP mRNA alternative splicing impacts the transcriptome at the genome-wide level. We found that the FD transcriptional signature was highly associated with biological functions related to the development of the nervous system. In addition, we identified target genes of kinetin, a plant cytokinin that corrects IKBKAP mRNA splicing and increases the expression of IKAP/hELP1. We identified this compound as a putative regulator of splicing factors and added new evidence for a sequence-specific correction of splicing. In conclusion, hOE-MSCs isolated from FD patients represent a promising avenue for modeling the altered genetic expression of FD, demonstrating a methodology that can be applied to a host of other genetic disorders to test the therapeutic potential of candidate molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Carrier Proteins / genetics
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Child
  • Dysautonomia, Familial / genetics*
  • Female
  • Genome-Wide Association Study / methods*
  • Humans
  • Kinetin / pharmacology
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • RNA Splicing / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptional Elongation Factors


  • Carrier Proteins
  • Elp1 protein, human
  • Transcriptional Elongation Factors
  • Kinetin