Elsevier

Genomics

Volume 90, Issue 1, July 2007, Pages 59-71
Genomics

Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene

https://doi.org/10.1016/j.ygeno.2007.03.005Get rights and content
Under an Elsevier user license
open archive

Abstract

The Aristaless-related homeobox gene (ARX) is one of the major genes causing X-linked mental retardation. We have been interested in the pathogenic mechanism of expanded polyalanine tract mutations in ARX. We showed that the c.304ins(GCG)7 mutation causing an increase from 16 to 23 alanines increased the propensity of ARX protein aggregation and a shift from nuclear to cytoplasmic localization. We proposed that mislocalization of ARX via cytoplasmic aggregation and subsequent degradation leads to a partial loss of function, contributing to the pathogenesis. We identified importin 13 (IPO13), a mediator of nuclear import for a variety of proteins, as a novel ARX interacting protein. We predicted that the transport of ARX by IPO13 from the cytoplasm to the nucleus might be disrupted by expanded polyalanine tract mutations, but our data showed that in both yeast and mammalian cells these mutant ARX proteins were still able to interact with IPO13. We established the nuclear localization regions of the ARX homeodomain that were required for the interaction with IPO13 and correct localization of the full-length ARX transcription factor to the nucleus.

Keywords

ARX
X-linked mental retardation
Mutation
Polyalanine tract
Yeast-2 hybrid
Coimmunoprecipitation
Nuclear localization sequence

Cited by (0)

1

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint first authors.