, Volume 13, Issue 1, pp 23–29

Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations

  • Ginam Cho
  • MacLean P. Nasrallah
  • Youngshin Lim
  • Jeffrey A. Golden
Original Article

DOI: 10.1007/s10048-011-0304-7

Cite this article as:
Cho, G., Nasrallah, M.P., Lim, Y. et al. Neurogenetics (2012) 13: 23. doi:10.1007/s10048-011-0304-7


Mutations in the Aristaless-related homeobox gene (ARX) are associated with a wide variety of neurologic disorders including lissencephaly, hydrocephaly, West syndrome, Partington syndrome, and X-linked intellectual disability with or without epilepsy. A genotype–phenotype correlation exists for ARX mutations; however, the molecular basis for this association has not been investigated. To begin understanding the molecular basis for ARX mutations, we tested the DNA binding sequence preference and transcriptional repression activity for Arx, deletion mutants and mutants associated with various neurologic disorders. We found DNA binding preferences of Arx are influenced by the amino acid sequences adjacent to the homeodomain. Mutations in the homeodomain show a loss of DNA binding activity, while the T333N and P353R homeodomain mutants still possess DNA binding activities, although less than the wild type. Transcription repression activity, the primary function of ARX, is reduced in all mutants except the L343Q, which has no DNA binding activity and does not functionally repress Arx targets. These data indicate that mutations in the homeodomain result in not only a loss of DNA binding activity but also loss of transcriptional repression activity. Our results provide novel insights into the pathogenesis of ARX-related disorders and possible directions to pursue potential therapeutic interventions.


ARXLissencephalyX-linked intellectual disabilityHomeodomain



Aristaless-related homeobox gene


Nuclear localization sequences


Systematic Evolution of Ligands by EXponential enrichment


X-linked lissencephaly with ambiguous genitalia


Electrophoretic mobility shift assays


Multiple EM for Motif Elucidation

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ginam Cho
    • 1
  • MacLean P. Nasrallah
    • 2
  • Youngshin Lim
    • 3
  • Jeffrey A. Golden
    • 1
    • 3
    • 4
  1. 1.Department of Pathology and Laboratory MedicineThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Neuroscience Graduate GroupPerelman School of Medicine at the University of PennsylvaniaPennsylvaniaUSA
  3. 3.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPennsylvaniaUSA
  4. 4.Abramson Research CenterPhiladelphiaUSA