Mechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for X linked hypopituitarism

Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro;...

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Bibliographic Details
Published inPLoS genetics Vol. 9; no. 3; p. e1003290
Main Authors Hughes, James, Piltz, Sandra, Rogers, Nicholas, McAninch, Dale, Rowley, Lynn, Thomas, Paul
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.03.2013
Public Library of Science (PLoS)
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Summary:Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro; however, it is less clear whether aggregation is of relevance to these diseases in vivo. To investigate this issue, we used targeted mutagenesis of embryonic stem (ES) cells to generate mice with a polyalanine expansion mutation in Sox3 (Sox3-26ala) that is associated with X-linked Hypopituitarism (XH) in humans. By investigating both ES cells and chimeric mice, we show that endogenous polyalanine expanded SOX3 does not form protein aggregates in vivo but rather is present at dramatically reduced levels within the nucleus of mutant cells. Importantly, the residual mutant protein of chimeric embryos is able to rescue a block in gastrulation but is not sufficient for normal development of the hypothalamus, a region that is functionally compromised in Sox3 null embryos and individuals with XH. Together, these data provide the first definitive example of a disease-relevant PA mutant protein that is both nuclear and functional, thereby manifesting as a partial loss-of-function allele.
Bibliography:Conceived and designed the experiments: PT JH SP NR DM. Performed the experiments: JH SP NR DM LR. Analyzed the data: JH PT SP NR DM LR. Wrote the paper: PT JH.
PT is supported by a Fellowship from Pfizer Australia. This does not alter the authors' adherence to all the PLOS Genetics policies on sharing data and materials.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003290