Journal Article

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

MacLean Pancoast Nasrallah, Ginam Cho, Jacqueline C. Simonet, Mary E. Putt, Kunio Kitamura and Jeffrey A. Golden

in Human Molecular Genetics

Volume 21, issue 5, pages 1090-1098
Published in print March 2012 | ISSN: 0964-6906
Published online November 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr538
Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression

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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 (ArxE), a mutation associated with infantile spasms and intellectual disabilities in humans. We found that although ArxE 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 ArxE 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.

Journal Article.  5858 words.  Illustrated.

Subjects: Genetics and Genomics

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