Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/58431
Type: Conference paper
Title: Unravelling the pathogenesis of the ARX homeobox mutations; role of IPO13
Author: Shoubridge, C.
Tan, M.
Fullston, T.
McGillivray, G.
Mancini, G.
Gecz, J.
Citation: Proceedings of 59th Annual meeting of the American Society of Human Genetics, 2009.
Publisher: American Society of Human Genetics
Publisher Place: USA
Issue Date: 2009
Conference Name: Annual meeting of the American Society of Human Genetics (59th : 2009 : Honolulu, Hawaii)
Statement of
Responsibility: 
C. Shoubridge, M. H. Tan, T. Fullston, G. McGillivray, G. Mancini and J. Gécz
Abstract: A frequently mutated gene causing X-linked intellectual disability is the Aristaless related homeobox (ARX) gene. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX are implicated in a range of intellectual disability phenotypes with or without additional features including epilepsy, infantile spasms, hand dystonia, lissencephaly, autism and dysarthria. Severe phenotypes, such as X-linked lissencephaly with abnormal genitalia (XLAG), are frequently observed in individuals with missense or nonsense mutations clustered in the conserved paired-type homeodomain. In this report we have identified a novel point mutation (c.1135C>A, p.R379S) in the homeodomain of ARX in a patient with infantile spasms and intellectual disability. We investigated this and other missense mutations (R332P, R332H, R332C, T333N and R379L) in residues of the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain, associated with XLAG and Proud syndrome phenotypes. The NLS regions in the ARX homeodomain are required for correct nuclear transport due to binding to the import protein, Importin 13 (IPO13). Moreover, the arginine residues involved with these mutations (position 5 and 52 of the paired-type homeodomain) are invariant in all 26 family members containing this homeodomain and are frequent sites of missense and non-sense mutations associated with a range of diseases. In this study we demonstrate missense mutations in either the N-terminal or C-terminal NLS regions of the ARX homeodomain cause significant disruption to nuclear localisation of the mutant transcription factor protein in vitro. Surprisingly, none of these mutations abolished the binding of the mutant protein to the nuclear transport protein IPO13, confirmed by co-immunoprecipitation and immmunoflorescence studies. Instead, endogenous IPO13 remained bound to the mutant ARX proteins, even in the RanGTP rich nuclear environment, which normally causes the release of cargo from IPO13. We conclude in addition to inadequate accumulation and distribution of the ARX transcription factor within the nucleus, the extended sequestration of the ARX cargo with IPO13 most likely contributes to the pathogenesis observed in patients with XLAG, Proud syndrome and infantile spasms caused by mutations in the residues of the NLS regions of the ARX homeodomain.
Rights: Copyright status unknown
RMID: 0020095788
Description (link): http://www.ashg.org/2009meeting/
Appears in Collections:Paediatrics publications

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