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

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Abstract

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.

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Abbreviations

ARX :

Aristaless-related homeobox gene

NLS:

Nuclear localization sequences

SELEX:

Systematic Evolution of Ligands by EXponential enrichment

XLAG:

X-linked lissencephaly with ambiguous genitalia

EMSA:

Electrophoretic mobility shift assays

MEME:

Multiple EM for Motif Elucidation

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Acknowledgements

This work was supported by NIH grant NS46616.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Ginam Cho & Jeffrey A. Golden

  2. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Pennsylvania, PA, USA

    MacLean P. Nasrallah

  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Pennsylvania, PA, USA

    Youngshin Lim & Jeffrey A. Golden

  4. Abramson Research Center, Room 516 g, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Jeffrey A. Golden

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  1. Ginam Cho
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  4. Jeffrey A. Golden
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Correspondence to Jeffrey A. Golden.

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Cho, G., Nasrallah, M.P., Lim, Y. et al. Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. Neurogenetics 13, 23–29 (2012). https://doi.org/10.1007/s10048-011-0304-7

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