New kid on the ID block

Kelly, Seth M.; Pak, ChangHui; Garshasbi, Masoud; Kuß, Andreas W.; Corbett, Anita H.; Moberg, Kenneth H.

doi:10.4161/rna.20187

Cited by 18 publications

(9 citation statements)

References 65 publications

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“…This included changes in CHGA, EPO, PAP, PTPA, TLE1, RN149 and TRIPB. The others have roles in immune system function (IgA, IL-3, TENA, CLC4K [ 49 , 50 ]), regulation of brain-specific mRNAs (ZC3HE [ 51 ]) transfer RNA processing (MRRP1 [ 52 ]) or cell adhesion and mobility (ARMC3 [ 53 ]). Previous studies have shown a reduction of IgA levels in subgroups of people with ASC although the study design did not test for sex differences [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome

et al. 2014

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BackgroundThe higher prevalence of Asperger Syndrome (AS) and other autism spectrum conditions in males has been known for many years. However, recent multiplex immunoassay profiling studies have shown that males and females with AS have distinct proteomic changes in serum.MethodsHere, we analysed sera from adults diagnosed with AS (males = 14, females = 16) and controls (males = 13, females = 16) not on medication at the time of sample collection, using a combination of multiplex immunoassay and shotgun label-free liquid chromatography mass spectrometry (LC-MSE). The main objective was to identify sex-specific serum protein changes associated with AS.ResultsMultiplex immunoassay profiling led to identification of 16 proteins that were significantly altered in AS individuals in a sex-specific manner. Three of these proteins were altered in females (ADIPO, IgA, APOA1), seven were changed in males (BMP6, CTGF, ICAM1, IL-12p70, IL-16, TF, TNF-alpha) and six were changed in both sexes but in opposite directions (CHGA, EPO, IL-3, TENA, PAP, SHBG). Shotgun LC-MSE profiling led to identification of 13 serum proteins which had significant sex-specific changes in the AS group and, of these, 12 were altered in females (APOC2, APOE, ARMC3, CLC4K, FETUB, GLCE, MRRP1, PTPA, RN149, TLE1, TRIPB, ZC3HE) and one protein was altered in males (RGPD4). The free androgen index in females with AS showed an increased ratio of 1.63 compared to controls.ConclusionTaken together, the serum multiplex immunoassay and shotgun LC-MSE profiling results indicate that adult females with AS had alterations in proteins involved mostly in lipid transport and metabolism pathways, while adult males with AS showed changes predominantly in inflammation signalling. These results provide further evidence that the search for biomarkers or novel drug targets in AS may require stratification into male and female subgroups, and could lead to the development of novel targeted treatment approaches.

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Section: Discussionmentioning

confidence: 99%

Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome

et al. 2014

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“…ZC3H14 (Zinc Finger CCCH-Type Containing 14) is an evolutionarily conserved, ubiquitously expressed polyadenosine RNA-binding protein (Leung et al, 2009). Mutations in the ZC3H14 gene cause an autosomal-recessive, non-syndromic form of intellectual disability (Al-Nabhani et al, 2018; S. Kelly et al, 2012; Pak et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

Jones

Rha

Kim

et al. 2020

Preprint

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ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), an evolutionarily conserved member of a class of tandem zinc finger (CCCH) polyadenosine (polyA) RNA binding proteins, is associated with a form of heritable, nonsyndromic autosomal recessive intellectual disability. Previous studies of a loss of function mouse model, Zc3h14Δex13/Δex13, provide evidence that ZC3H14 is essential for proper brain function, specifically for working memory. To expand on these findings, we analyzed the dendrites and dendritic spines of hippocampal neurons from Zc3h14Δex13/Δex13 mice, both in situ and in vitro. These studies reveal that loss of ZC3H14 is associated with a decrease in total spine density in hippocampal neurons in vitro as well as in the dentate gyrus of 5-month old mice analyzed in situ. This reduction in spine density in vitro results from a decrease in the number of mushroom-shaped spines, which is rescued by exogenous expression of ZC3H14. We next performed biochemical analyses of synaptosomes prepared from whole wild-type and Zc3h14Δex13/Δex13 mouse brains to determine if there are changes in steady state levels of postsynaptic proteins upon loss of ZC3H14. We found that ZC3H14 is present within synaptosomes and that a crucial postsynaptic protein, CaMKIIα, is significantly increased in these synaptosomal fractions upon loss of ZC3H14. Together, these results demonstrate that ZC3H14 is necessary for proper dendritic spine density in cultured hippocampal neurons and in some regions of the mouse brain. These findings provide insight into how a ubiquitously expressed RNA binding protein leads to neuronal-specific defects that result in brain dysfunction.

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“…Mutations in the ZC3H14 gene cause autosomal-recessive intellectual disability, indicating that ZC3H14 plays a critical role in the brain (50,51). Like Nab2, ZC3H14 regulates poly(A) tail length (49).…”

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confidence: 99%

Evolutionarily Conserved Polyadenosine RNA Binding Protein Nab2 Cooperates with Splicing Machinery To Regulate the Fate of Pre-mRNA

Soucek

Zeng

Bellur

et al. 2016

Molecular and Cellular Biology

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g Numerous RNA binding proteins are deposited onto an mRNA transcript to modulate posttranscriptional processing events ensuring proper mRNA maturation. Defining the interplay between RNA binding proteins that couple mRNA biogenesis events is crucial for understanding how gene expression is regulated. To explore how RNA binding proteins control mRNA processing, we investigated a role for the evolutionarily conserved polyadenosine RNA binding protein, Nab2, in mRNA maturation within the nucleus. This study reveals that nab2 mutant cells accumulate intron-containing pre-mRNA in vivo. We extend this analysis to identify genetic interactions between mutant alleles of nab2 and genes encoding a splicing factor, MUD2, and RNA exosome, RRP6, with in vivo consequences of altered pre-mRNA splicing and poly(A) tail length control. As further evidence linking Nab2 proteins to splicing, an unbiased proteomic analysis of vertebrate Nab2, ZC3H14, identifies physical interactions with numerous components of the spliceosome. We validated the interaction between ZC3H14 and U2AF2/U2AF 65 . Taking all the findings into consideration, we present a model where Nab2/ZC3H14 interacts with spliceosome components to allow proper coupling of splicing with subsequent mRNA processing steps contributing to a kinetic proofreading step that allows properly processed mRNA to exit the nucleus and escape Rrp6-dependent degradation. Gene expression is temporally and spatially regulated to produce a precise protein expression profile that dictates the function of each cell. Although much of this control occurs at the level of transcription, both co-and posttranscriptional events also play key regulatory roles. Newly synthesized mRNAs undergo numerous processing events, including 5= capping, splicing, 3=-end processing, and export to the cytoplasm (1, 2). Ensuring the synchrony of mRNA biogenesis requires RNA binding proteins that not only perform the processing tasks but also couple the events to ensure that only properly processed mRNAs are available for translation in the cytoplasm (3).Key processing events that must be coordinated include splicing and 3=-end processing. Although steps in mRNA processing are often depicted and studied as separate events, there is a growing body of evidence that these processing events are intimately coupled to one another (2). For example, splicing and 3=-end processing are coupled in humans as mutations in splice site and polyadenylation consensus sequences mutually disrupt both splicing and polyadenylation (4-6). In addition, a number of splicing factors copurify with the 3=-end processing complex (7-10). For example, there is evidence that the splicing factor U2AF2/ U2AF 65 functions as a bridge between the U2 snRNP and the 3=-end processing machinery (11,12). Given the extensive coupling between RNA processing steps, it is important to consider the consequences when one step of the process is disrupted in vivo. Cells have developed numerous overlapping mechanisms to ensure that faulty mRNA transcripts are not...

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New kid on the ID block

Cited by 18 publications

References 65 publications

Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome

Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome

The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

Evolutionarily Conserved Polyadenosine RNA Binding Protein Nab2 Cooperates with Splicing Machinery To Regulate the Fate of Pre-mRNA

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