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

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dc.contributor.authorHughes, J.
dc.contributor.authorPiltz, S.
dc.contributor.authorRogers, N.
dc.contributor.authorMcAninch, D.
dc.contributor.authorRowley, L.
dc.contributor.authorThomas, P.
dc.contributor.editorCamper, S.
dc.date.issued2013
dc.descriptionExtent: 9 p.
dc.description.abstractPolyalanine 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.
dc.description.statementofresponsibilityJames Hughes Sandra Piltz, Nicholas Rogers, Dale McAninch, Lynn Rowley and Paul Thomas
dc.identifier.citationPLoS Genetics, 2013; 9(3):1-9
dc.identifier.doi10.1371/journal.pgen.1003290
dc.identifier.issn1553-7390
dc.identifier.issn1553-7404
dc.identifier.orcidMcAninch, D. [0000-0001-9735-6553]
dc.identifier.urihttp://hdl.handle.net/2440/79620
dc.language.isoen
dc.publisherPublic Library of Science
dc.rightsCopyright: © 2013 Hughes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pgen.1003290
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectCell Nucleus
dc.subjectHypopituitarism
dc.subjectDisease Models, Animal
dc.subjectPeptides
dc.subjectEmbryonic Development
dc.subjectMutagenesis
dc.subjectGenetic Diseases, X-Linked
dc.subjectMutant Proteins
dc.subjectProteostasis Deficiencies
dc.subjectAlleles
dc.subjectEmbryonic Stem Cells
dc.subjectSOXB1 Transcription Factors
dc.titleMechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for x linked hypopituitarism
dc.typeJournal article
pubs.publication-statusPublished

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