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Molecular Pathology of Polyalanine Expansion Disorders: New Perspectives from Mouse Models

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Book cover Tandem Repeats in Genes, Proteins, and Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1017))

Abstract

Disease-causing polyalanine (PA) expansion mutations have been identified in nine genes, eight of which encode transcription factors (TFs) with important roles in development. In vitro and cell overexpression studies have shown that expanded PA tracts result in protein misfolding and the formation of aggregates. This feature of PA proteins is reminiscent of the related polyglutamine (PQ) disease proteins, which have been shown to cause disease via a gain-of-function (GOF) mechanism. However, in sharp contrast to PQ disorders, the disease phenotypes associated with PA mutations are more consistent with a LOF and/or mild GOF mechanism, suggesting that their molecular pathology is inherently different to PQ disorders. Elucidating the cellular impact of PA mutations in vivo has been difficult to address as, unlike the late-onset polyglutamine disorders, all PA disorders associated with TF gene mutations are congenital. However, in recent years, significant advances have been made through the analysis of engineered (knock-in) and spontaneous PA mouse models. Here we review these recent findings and propose an updated model of the molecular and cellular mechanism of PA disorders that incorporates both LOF and GOF features.

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Authors and Affiliations

  1. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia

    James N. Hughes & Paul Q. Thomas

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  1. James N. Hughes
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  2. Paul Q. Thomas
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  1. , Dept. of Biochemistry and Molecular Biol, The University of Melbourne, Flemington Road 30, Parkville, 3010, Victoria, Australia

    Danny M. Hatters

  2. Florey Neuroscience Institutes, and Mental Health, The University of Melbourne, Royal Parade, Parkville, 3010, Victoria, Australia

    Anthony J. Hannan

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Hughes, J.N., Thomas, P.Q. (2013). Molecular Pathology of Polyalanine Expansion Disorders: New Perspectives from Mouse Models. In: Hatters, D., Hannan, A. (eds) Tandem Repeats in Genes, Proteins, and Disease. Methods in Molecular Biology, vol 1017. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-438-8_10

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  • DOI: https://doi.org/10.1007/978-1-62703-438-8_10

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-437-1

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