A novel role of fragile X mental retardation protein in pre-mRNA alternative splicing through RNA-binding protein 14

Zhou, Lin-Tao; Ye, Shun-Hua; Yang, Haixuan; Zhou, Yongting; Zhao, Qi‐Hua; Sun, Weiwen; Gao, Mei-Mei; Yi, Yong‐Hong; Long, Yue-Sheng

doi:10.1016/j.neuroscience.2017.02.044

Cited by 50 publications

(42 citation statements)

References 64 publications

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“…Recent work from zebrafish and mouse FXS models shows FMRP alters RNA-editing via interaction with the adenosine deaminase ADAR , supporting earlier Drosophila studies (Table 1) [6,7]. In the mouse FXS model, FMRP also works with RNA-binding protein 14 (RBM14) in pre-mRNA alternative splicing (Table 1) [8]. FMRP has long been associated with the microRNA pathway, and recent studies suggest key interactions in circuit plasticity and behavioral output in Drosophila (Table 1) [9,10].…”

Section: Overview Of Expanding Fmrp Functionssupporting

confidence: 64%

“…While most recent studies continue to identify new FMRP mRNA targets (Table 2), other work reveals new FMRP protein partners in an ever-broadening arena of biology (Table 3). Although some interactions support canonical roles in translation control, others have expanded FMRP biology to a dizzying scale spanning from chromatin-binding to channel-binding (Table 1) [3,4,6,7,8]. Considerable work has shown the importance of channel-binding interactions in FXS, especially for disease state hyperexcitability.…”

Section: Part V: Future Directionsmentioning

confidence: 99%

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Multifarious Functions of the Fragile X Mental Retardation Protein

2017

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Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder, results from loss of Fragile X Mental Retardation Protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of involvement in RNA-, channel- and protein-binding that modulates calcium signaling, activity-dependent critical period development and excitation-inhibition neural circuitry balance. This article contextualizes three years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles; to determine whether FMRP has a multitude of unrelated functions, or combinatorial mechanisms can explain its multifaceted existence.

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Section: Overview Of Expanding Fmrp Functionssupporting

confidence: 64%

Section: Part V: Future Directionsmentioning

confidence: 99%

Multifarious Functions of the Fragile X Mental Retardation Protein

2017

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“…Concerning RMB14 , it acts as a general nuclear co‐activator and RNA splicing, reported as an interacting protein with FMRP (associated with Fragile X Syndrome, MIM 300624). RBM14 and FMRP are partially co‐localized in the nuclei of hippocampal neurons and may be associated with normal brain function and FMRP ‐related neurological disorders [Zhou et al, ]. Two other patients with ASD and ID were described harboring missense variants in this gene [Lelieveld et al, ; De Rubeis et al, ], but our ASD patient (F10637‐1) with RMB14 variant has no comorbidity, and also harbors a de novo variant on NCL , a widely expressed gene involved in the control of transcription of ribosomal RNA [Srivastava, Fleming, Pollard, & Burns, ].…”

Section: Discussionmentioning

confidence: 95%

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

et al. 2019

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Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta‐analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta‐analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss‐of‐function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non‐previous ASD genes, we prioritized PRPF8 and RBM14. Meta‐analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P‐value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra‐hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199–206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).

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“…FMRP promoted RBM14 binding to its mRNA targets. Knockdown of either FMRP or RBM14 altered the relative skipping/inclusion ratio of targeted exons including those of Protrudin (ZFYVE27, kinesin adapter) and microtubule-associated protein TAU [150]. FMRP was also shown to bind chromatin through its tandem Tudor domain and participate in DNA damage response (DDR) in a chromatin-binding-dependent manner.…”

Section: Neurodevelopmental Defectsmentioning

confidence: 99%

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

Ravanidis

Kattan

Doxakis

2018

IJMS

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The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

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A novel role of fragile X mental retardation protein in pre-mRNA alternative splicing through RNA-binding protein 14

Cited by 50 publications

References 64 publications

Multifarious Functions of the Fragile X Mental Retardation Protein

Multifarious Functions of the Fragile X Mental Retardation Protein

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

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