Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/43835
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Type: Journal article
Title: Aristaless-related homeobox gene, the gene responsible for west syndrome and related disorders, is a groucho/transducin-like enhancer of split dependent transcriptional repressor
Author: McKenzie, O.
Ponte, I.
Mangelsdorf, M.
Finnis, M.
Colasante, G.
Shoubridge, C.
Stifani, S.
Gecz, J.
Broccoli, V.
Citation: Neuroscience, 2007; 146(1):236-247
Publisher: Pergamon-Elsevier Science Ltd
Issue Date: 2007
ISSN: 0306-4522
1873-7544
Statement of
Responsibility: 
O. McKenzie, I. Ponte, M. Mangelsdorf, M. Finnis, G. Colasante, C. Shoubridge, S. Stifani, J. Gécz, V. Broccoli
Abstract: Aristaless-related homeobox gene (ARX) is an important paired-type homeobox gene involved in the development of human brain. The ARX gene mutations are a significant contributor to various forms of X-chromosome-linked mental retardation with and without additional features including epilepsy, lissencephaly with abnormal genitalia, hand dystonia or autism. Here we demonstrate that the human ARX protein is a potent transcriptional repressor, which binds to Groucho/transducin-like enhancer of split (TLE) co-factor proteins and the TLE1 in particular through its octapeptide (Engrailed homology repressor domain (eh-1) homology) domain. We show that the transcription repression activity of ARX is modulated by two strong repression domains, one located within the octapeptide domain and the second in the region of the polyalanine tract 4, and one activator domain, the aristaless domain. Importantly, we show that the transcription repression activity of ARX is affected by various naturally occurring mutations. The introduction of the c.98T>C (p.L33P) mutation results in the lack of binding to TLE1 protein and relaxed transcription repression. The introduction of the two most frequent ARX polyalanine tract expansion mutations increases the repression activity in a manner dependent on the number of extra alanines. Interestingly, deletions of alanine residues within polyalanine tracts 1 and 2 show low or no effect. In summary we demonstrate that the ARX protein is a strong transcription repressor, we identify novel ARX interacting proteins (TLE) and offer an explanation of a molecular pathogenesis of some ARX mutations, including the most frequent ARX mutations, the polyalanine tract expansion mutations, c.304ins(GCG)7 and c.428_451dup.
Keywords: Brain; Neurons; Cells, Cultured; Animals; Humans; Mice; Transducin; Alanine; Homeodomain Proteins; Transcription Factors; Repressor Proteins; In Situ Hybridization; Transfection; Immunoprecipitation; Age Factors; Transcription, Genetic; Gene Expression Regulation, Developmental; Mutation; Embryo, Mammalian; Enhancer Elements, Genetic
Description: Copyright © 2007 IBRO Published by Elsevier Ltd.
RMID: 0020070727
DOI: 10.1016/j.neuroscience.2007.01.038
Description (link): http://www.elsevier.com/wps/find/journaldescription.cws_home/468/description#description
Appears in Collections:Paediatrics publications

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