De novo variants in
            <i>CELF2</i>
            that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy

Itai, Toshiyuki; Hamanaka, Kohei; Sasaki, Kazunori; Wagner, Matias; Kotzaeridou, Urania; Brösse, Ines; Ries, Markus; Kobayashi, Yu; Tohyama, Jun; Kato, Mitsuhiro; Ong, Winnie Peitee; Chew, Hui Bein; Rethanavelu, Kavitha; Ranza, Emmanuelle; Blanc, Xavier; Uchiyama, Yuri; Tsuchida, Naomi; Fujita, Atsushi; Azuma, Yoshiteru; Koshimizu, Eriko; Mizuguchi, Takeshi; Takata, Atsushi; Miyake, Noriko; Takahashi, Hidehisa; Miyagi, Etsuko; Tsurusaki, Yoshinori; Doi, Hiroshi; Taguri, Masataka; Antonarakis, Stylianos E.; Nakashima, Mitsuko; Saitsu, Hirotomo; Miyatake, Satoko; Matsumoto, Naomichi

doi:10.1002/humu.24130

Cited by 25 publications

(17 citation statements)

References 26 publications

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“…Indeed, our results show that individuals with perturbed CELF2 transport present with clinical features of ASD, speech delay, ID, epilepsy, and cortical malformations. During the preparation of this manuscript, an independent study (Itai et al, 2021) reported five more patients with missense (same positions also found in this study), frameshift, and splice-site variants, which similarly perturbed CELF2 transport to different degrees and caused overlapping clinical traits with varying levels of severity. This study and ours highlight an essential role of CELF2 nucleocytoplasmic shuttling in brain development and suggest that the pathological variants are likely to have an effect on additional developmental processes beyond neurogenesis.…”

Section: Discussionsupporting

confidence: 71%

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates

et al. 2021

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Section: Discussionsupporting

confidence: 71%

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates

et al. 2021

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“…and recruits proneural factors (such as Neurog2, Neurod1, and Tbr2) and neurodevelopmental disease-associated mRNAs into processing bodies for translational repression, thereby maintaining NPC identity and controlling the NPC fate decision (MacPherson et al, 2021). Itai et al (2021) also noticed an aberrant cytoplasmic accumulation of CELF2 after transfecting human HEK293T cells and African green monkey COS7 cells with plasmids containing disease-associated missense and frameshift variants. These results confirm the necessity of post-transcriptional regulation, and specifically of cytoplasmicnuclear shuttling activity of CELF2, for the maintenance of progenitor self-renewal properties.…”

Section: Embryonic Lethal Abnormal Vision-like and Cugbp Elavl-like Familymentioning

confidence: 97%

“…The CELF and ELAVL families are linked to neural development and as such the polymorphisms in CELF and ELAVL genes, as well as alterations in the functional properties of their respective proteins, are associated with neurodevelopmental disorders ( Popovitchenko et al, 2020 ). For example, Itai et al (2021) have identified for the first-time that heterozygous CELF2 mutations in unrelated individuals resulted in a range of overlapping clinical symptoms. These symptoms include neurodevelopmental and epileptic encephalopathy, intellectual disability, and autistic behavior – all to varying severity.…”

Section: Post-transcriptional Regulation Mrnas Poised For Translation and Rna-binding Proteinsmentioning

confidence: 99%

“…These symptoms include neurodevelopmental and epileptic encephalopathy, intellectual disability, and autistic behavior – all to varying severity. This suggests that CELF2 , and specifically its dosage, is critical to normal neuronal function ( Itai et al, 2021 ). Another recent study has corroborated previous findings by identifying additional de novo heterozygous missense CELF2 mutations in RRM3 in patients with neurodevelopmental defects and cortical malformations.…”

Section: Post-transcriptional Regulation Mrnas Poised For Translation and Rna-binding Proteinsmentioning

confidence: 99%

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Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

Salamon

Rašin

2022

Front. Neurosci.

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The human neocortex is undoubtedly considered a supreme accomplishment in mammalian evolution. It features a prenatally established six-layered structure which remains plastic to the myriad of changes throughout an organism’s lifetime. A fundamental feature of neocortical evolution and development is the abundance and diversity of the progenitor cell population and their neuronal and glial progeny. These evolutionary upgrades are partially enabled due to the progenitors’ higher proliferative capacity, compartmentalization of proliferative regions, and specification of neuronal temporal identities. The driving force of these processes may be explained by temporal molecular patterning, by which progenitors have intrinsic capacity to change their competence as neocortical neurogenesis proceeds. Thus, neurogenesis can be conceptualized along two timescales of progenitors’ capacity to (1) self-renew or differentiate into basal progenitors (BPs) or neurons or (2) specify their fate into distinct neuronal and glial subtypes which participate in the formation of six-layers. Neocortical development then proceeds through sequential phases of proliferation, differentiation, neuronal migration, and maturation. Temporal molecular patterning, therefore, relies on the precise regulation of spatiotemporal gene expression. An extensive transcriptional regulatory network is accompanied by post-transcriptional regulation that is frequently mediated by the regulatory interplay between RNA-binding proteins (RBPs). RBPs exhibit important roles in every step of mRNA life cycle in any system, from splicing, polyadenylation, editing, transport, stability, localization, to translation (protein synthesis). Here, we underscore the importance of RBP functions at multiple time-restricted steps of early neurogenesis, starting from the cell fate transition of transcriptionally primed cortical progenitors. A particular emphasis will be placed on RBPs with mostly conserved but also divergent evolutionary functions in neural progenitors across different species. RBPs, when considered in the context of the fascinating process of neocortical development, deserve to be main protagonists in the story of the evolution and development of the neocortex.

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“…All six members have a similar structure that includes three RRMs (RNA Recognition Motifs), two in the N-terminal and one in the C-terminal, as well as a divergent linker region that can improve RBP binding affinity through conformational variations. The nuclear localization signal, which comprises a lysine/arginine-rich region in the C terminal and a region important for nuclear export in the linker domain, are two other key structures [6,13,14]. A serine/threonine-rich phosphorylation area within the CELF1 and CELF2 linker domains could change their affinity for binding to target mRNAs [15,16].…”

Section: General Characteristics Of the Celf Protein Familymentioning

confidence: 99%

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

Aghdam

Jave‐Suárez

2021

IJMS

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Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

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De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy

Cited by 25 publications

References 26 publications

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

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