NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation

Lin, Jun; Frints, Suzanna G.M.; Duhamel, Hein; Herold, Andrea; Abad-Rodrigues, Jose; Dotti, Carlos G.; Izaurralde, Elisa; Marynen, Peter; Froyen, Guy

doi:10.1016/s0960-9822(01)00419-5

Cited by 66 publications

(100 citation statements)

References 40 publications

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“…47 This gene is involved in mRNA nuclear transportation and is specifically expressed in neurites of hippocampal neurons. 48 Although the minigene assay showed an altered splicing effect of the N96S variant, our familial segregation analysis does not support a major role of this variant in SCZ.…”

Section: Splicing Alterations Of Gaba R Genes In Autismcontrasting

confidence: 65%

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

et al. 2012

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A large-scale sequencing screen of X-linked synaptic genes in individuals with autism spectrum disorder (ASD) or schizophrenia (SCZ), two common neurodevelopmental disorders, identified many variants most of which have no easily predictable effect on gene function. In this report, we evaluated the impact of these rare missense and silent variants on gene splicing. For this purpose, we used complementary in silico analyses, in vitro minigene-based assays and RNA prepared from lymphoblastoid cells derived from patients with these mutations. Our goal was to identify the variants which might either create or disrupt an acceptor splice site, a donor splice site or an exonic splicing enhancer, thus leading to aberrant splicing that could be involved in the pathogenesis of ASD or SCZ. We identified truncating mutations in distinct X-linked gamma-aminobutyric acid A (GABA A) receptor subunit-encoding genes, GABRQ and GABRA3, in two different families. Furthermore, missense and silent variants in nuclear RNA export factor 5 and histone deacetylase 6 were shown to partially disrupt the protein. While genes from the GABAergic pathway have previously been thought to be involved in the pathophysiology of ASD, this is the first report of ASD patients with truncating mutations in GABA receptors genes.

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Section: Splicing Alterations Of Gaba R Genes In Autismcontrasting

confidence: 65%

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

et al. 2012

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“…Nova proteins regulate neuronal pre-mRNA splicing by directly binding to RNA (Ule et al, 2003). Another putative RNA export factor, NXF5, is absent in some patients of X-linked mental retardation (Frints et al, 2003;Jun et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

RNA association and nucleocytoplasmic shuttling by ataxin-1

Irwin

Vandelft

Pinchev

et al. 2005

Journal of Cell Science

113

110

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Spinocerebellar ataxia type 1 (SCA1) is a dominant neurodegenerative disease caused by the expression of mutant ataxin-1 containing an expanded polyglutamine tract. Ataxin-1 is a nuclear protein that localizes to punctate inclusions similar to neuronal nuclear inclusions seen in many polyglutamine expansion disease proteins. We demonstrate that ataxin-1 localization to inclusions and inclusion dynamics within the nucleus are RNA and transcription dependent, but not dependent on the polyglutamine tract. Ataxin-1 nuclear inclusions are distinct from other described nuclear bodies but recruit the mRNA export factor, TAP/NXF1, in a manner that is enhanced by cell heat shock. By FRAP protein dynamic studies in live cells, we found that wild-type, but not mutant, ataxin-1 was capable of nuclear export. These results suggest that the normal role of ataxin-1 may be in RNA processing, perhaps nuclear RNA export. Thus, nuclear retention of mutant ataxin-1 may be an important toxic gain of function in SCA1 disease.

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“…It was therefore surprising, when it was shown that at least one of the NXF proteins (NXF5) localizes exclusively to the cytoplasm. This protein is expressed in neuronal cells, and mutations in this gene have been linked to a hereditary form of male mental retardation (Jun et al 2001;Frints et al 2003). The current hypothesis is that this protein plays a role in neuronal mRNA localization or translation or both.…”

Section: Discussionmentioning

confidence: 99%

Tap and NXT promote translation of unspliced mRNA

Jin¹,

Guzik²,

Bor³

et al. 2003

Genes Dev.

141

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Tap has been proposed to play a role in general mRNA export and also functions in expression of RNA with retained introns that contain the MPMV CTE (constitutive transport element). Tap forms a functional heterodimer with NXT/p15. We have previously demonstrated that unspliced intron-containing CTE RNA is efficiently exported to the cytoplasm in mammalian cells. Here we show that Tap and NXT proteins function together to enhance translation of proteins from the exported CTE RNA. Pulse chase experiments show that Tap/NXT significantly increases the rate of protein synthesis. Sucrose gradient analysis demonstrates that Tap and NXT efficiently shift the unspliced RNA into polyribosomal fractions. Furthermore, Tap, but not NXT is detected in polyribosomes. Taken together, our results indicate that Tap and NXT serve a role in translational regulation of RNA after export to the cytoplasm. They further suggest that Tap/NXT may play a role in remodeling of cytoplasmic RNP complexes, providing a link between export pathways and cytoplasmic fate. In higher eukaryotes, the majority of genes produce nascent mRNA transcripts that contain several introns. Export of incompletely spliced RNAs with retained introns from these genes would potentially result in translation of aberrant proteins that could have deleterious effects on the cells. However, cells appear to have developed checkpoints to ensure that only fully spliced mRNAs are exported and expressed (Chang and Sharp 1989;Legrain and Rosbash 1989).Retroviruses use special mechanisms that allow unspliced and incompletely spliced (that is, intron-containing) viral transcripts to exit the nucleus and escape cellular proofreading mechanisms (Hammarskjöld 1997(Hammarskjöld , 2001). Replication of all of these viruses requires the cytoplasmic expression of intron-containing forms of the initial, genome-length viral RNA transcript, because the unspliced RNA serves both as the mRNA for the viral Gag and GagPol proteins and as the RNA that is packaged into viral particles (Berkowitz et al. 1996). In complex retroviruses such as HIV-1, export of unspliced and incompletely spliced RNA relies on the interaction of the viral Rev protein with a structured RNA sequence present in these RNAs, the Rev responsive element (RRE; Hadzopoulou-Cladaras et al. 1989; Hammarskjold et al. 1989;Malim et al. 1989; Pollard and Malim 1998).The resulting mRNP complex is exported by virtue of the nuclear export signal (NES) in Rev that interacts with the cellular export receptor Crm1 (Fornerod et al. 1997;Neville et al. 1997).Simple retroviruses do not encode an Rev-like transacting protein, and export of their unspliced RNA relies on the interaction of cis-acting RNA elements directly with cellular factors. The first element of this kind was identified in the simian type D retrovirus Mason Pfizer Monkey Virus (MPMV) and was given the name CTE (constitutive transport element; Bray et al. 1994; Ernst et al. 1997a,b; Hammarskjold 2001), because its interaction with cellular factors results in constitut...

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NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation

Cited by 66 publications

References 40 publications

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

RNA association and nucleocytoplasmic shuttling by ataxin-1

Tap and NXT promote translation of unspliced mRNA

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