Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression

Hum Mol Genet. 2012 Mar 1;21(5):1090-8. doi: 10.1093/hmg/ddr538. Epub 2011 Nov 22.


Polyalanine (poly-A) tracts exist in 494 annotated proteins; to date, expansions in these tracts have been associated with nine human diseases. The pathogenetic mechanism by which a poly-A tract results in these various human disorders remains uncertain. To understand the role of this mutation type, we investigated the change in functional properties of the transcription factor Arx when it has an expanded poly-A tract (Arx(E)), a mutation associated with infantile spasms and intellectual disabilities in humans. We found that although Arx(E) functions normally in the dorsal brain, its function in subpallial-derived populations of neurons is compromised. These contrasting functions are associated with the misregulation of Arx targets through the loss of the ability of Arx(E) to interact with the Arx cofactor Tle1. Our data demonstrate a novel mechanism for poly-A expansion diseases: the misregulation of a subset of target genes normally regulated by a transcription factor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / embryology*
  • Brain / metabolism
  • Cell Movement
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Co-Repressor Proteins
  • DNA / metabolism
  • DNA Repeat Expansion*
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Interneurons / physiology
  • Mice
  • Mutation
  • Neurogenesis
  • Neurons / physiology*
  • Poly A / genetics*
  • Prosencephalon / embryology
  • Prosencephalon / metabolism
  • Protein Binding
  • Repressor Proteins / metabolism
  • Telencephalon / cytology
  • Telencephalon / embryology
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*


  • ARX protein, mouse
  • Co-Repressor Proteins
  • Homeodomain Proteins
  • Repressor Proteins
  • Tle1 protein, mouse
  • Transcription Factors
  • Poly A
  • DNA