Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/42972
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Type: Journal article
Title: Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation
Author: Wong, J.
Farlie, P.
Holbert, S.
Lockhart, P.
Thomas, P.
Citation: Frontiers in Bioscience, 2007; 12(6):2085-2095
Publisher: Frontiers in Bioscience Inc
Issue Date: 2007
ISSN: 1093-9946
1093-4715
Organisation: Centre for the Molecular Genetics of Development
Statement of
Responsibility: 
Jacqueline Wong, Peter Farlie, Sebastien Holbert, Paul Lockhart and Paul Q. Thomas
Abstract: Polyalanine expansion mutations have been identified in eight transcription factors that are associated with a range of congenital disorders. While some of these mutant proteins have been shown to generate cellular aggregates in heterologous cell lines, little is known about the mechanism by which these aggregates cause disease. Here we examine the aggregation and functional properties of the two known polyalanine expansion mutations associated with X-linked Hypopituitarism (XH), SOX3(22Ala) and SOX3(26Ala), which contain an additional seven and eleven alanine residues, respectively. SOX3(22Ala) and SOX3(26Ala) proteins form cytoplasmic aggregates and nuclear inclusions in transiently transfected COS-7 and CHO K1 cells, and in transfected explant cultures of chick neural epithelium. SOX3(26Ala) exhibits a more potent aggregation phenotype, resulting in significantly more cells with dispersed cytoplasmic and large perinuclear aggregates. SOX3(22Ala) and SOX3(26Ala) protein aggregates exhibit the key properties of aggresomes including vimentin redistribution, colocalisation with the Microtubule Organising Centre and sensitivity to microtubule disruption. This is the first time that aggresomes have been implicated in the aetiology of a polyalanine expansion disorder, suggesting that XH and protein conformation disorders may become manifest through similar pathological mechanisms. Further, we show that mutant SOX3 proteins have impaired transcriptional activity and reduced capacity to inhibit beta-catenin/TCF-mediated transcription. These data suggest that deregulation of SOX3 target genes and inappropriate canonical Wnt signaling in central nervous system (CNS) progenitors may also contribute to dysfunction of the hypothalamic-pituitary axis in XH patients.
Keywords: Animals; Cercopithecus aethiops; Humans; Chick Embryo; COS Cells; Cell Nucleus Structures; Hypopituitarism; Peptides; Transcription Factors; DNA-Binding Proteins; High Mobility Group Proteins; DNA Repeat Expansion; Genetic Diseases, X-Linked; Transcriptional Activation; SOXB1 Transcription Factors; Cytoplasmic Structures; beta Catenin; Male
RMID: 0020070139
DOI: 10.2741/2213
Appears in Collections:Molecular and Biomedical Science publications

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